Doses and methods for administering telavancin

ABSTRACT

Doses and methods for administering telavancin or a pharmaceutically-acceptable salt thereof to a human patient having an infection caused by  Staphylococcus aureus , such as bacteremia, pneumonia, endocarditis, osteomyelitis, a prosthetic joint infection or a complicated skin and skin structure infection, are disclosed. Also disclosed are methods for treating an infection caused by  Staphylococcus aureus  in a human patient using telavancin or a pharmaceutically-acceptable salt thereof. The dose of telavancin administered to the patient is determined, in part, by the weight and creatinine clearance of the patient.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application No.62/119,592, filed on Feb. 23, 2015; the entire disclosure of which isincorporated herein by reference in its entirety.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to novel doses and methods foradministering telavancin or a pharmaceutically-acceptable salt thereofto a human patient having an infection caused by Staphylococcus aureus,such as bacteremia, pneumonia, endocarditis, osteomyelitis, a prostheticjoint infection or a complicated skin and skin structure infection. Thepresent invention also relates to methods for treating an infectioncaused by Staphylococcus aureus in a human patient using telavancin or apharmaceutically-acceptable salt thereof. In the present invention, thedose of telavancin administered to the patient is determined, in part,by the weight and creatinine clearance of the patient.

2. State of the Art

Telavancin is a lipoglycopeptide antibacterial agent used to treatinfections caused by susceptible Gram-positive bacteria in humanpatients, such as complicated skin and skin structure infections (cSSSI)and hospital-acquired and ventilator-associated bacterial pneumonia(HABP/VABP). See, for example, Pace et al., Curr. Opin. Investig. Drugs(2005) 6(2):216-25; Drugs R D. (2006) 7(6):384-8; Kanafani, Expert Rev.Anti. Infect. Ther. (2006) 4(5):743-9; Attwood et al., Am. J. HealthSyst. Pharm. (2007) 64(22):2335-48; Laohavaleeson et al., Expert Opin.Investig. Drugs (2007) 16(3):347-57; Nannini et al., Expert Opin.Pharmacother. (2008) 9(12):2197-207; Charneski et al., Ann.Pharmacother. (2009) 43(5):928-38; Rubinstein et al., Expert Opin.Pharmacother. (2011) 12(17):2737-50; Nannini et al., Expert Review ofAntiinfective Therapy (2012) 10(8):847-54. Telavancin is also beingevaluated for use in treating complicated bacteremia caused byStaphylococcus aureus.

For most cSSSI and HABP/VABP patients with normal renal function, thecurrently-recommended dose of telavancin is 10 mg/kg (free baseequivalents) every 24 hours. See, for example, VIBATIV® (telavancin)Prescribing Information; Revised March 2014. However, because telavancinis eliminated primarily by the kidney, a dose adjustment is recommendedfor patients whose creatinine clearance is less than or equal to 50mL/min. For adult patients having a creatinine clearance between 30mL/min and 50 mL/min, the currently-recommended dose of telavancin is7.5 mg/kg every 24 hours; and for adult patients with a creatinineclearance between 10 mL/min and less than 30 mL/min, the dose is furtheradjusted to 10 mg/kg every 48 hours.

Even with the prior dose adjustments for adult patients with renalimpairment, increased rates of acute kidney injury and mortality (inHABP/VABP patients with moderate or severe renal impairment) wereobserved in clinical trials for telavancin compared to vancomycin. See,for example, Rubinstein et al., Expert Opin. Pharmacother. (2011)12(17):2737-50.

Accordingly, a need exists for new doses and methods for administeringtelavancin to human patients that are predicted to reduce the overallincidence of acute kidney injury and mortality in such patients whilemaintaining the antibacterial efficacy of telavancin.

SUMMARY OF THE INVENTION

The present invention provides new doses and methods for administeringtelavancin or a pharmaceutically-acceptable salt thereof to a humanpatient having an infection caused by Staphylococcus aureus, such asbacteremia, pneumonia, endocarditis, osteomyelitis, a prosthetic jointinfection or a complicated skin and skin structure infection.

In one embodiment, the present invention is based, in part, on thediscovery that acute kidney injury and mortality are predicted to bereduced and antibacterial efficacy is predicted to be maintained if (i)the dose of telavancin administered to the patient is about 25 percentlower than the prior dose based on the patient's creatinine clearanceand (ii) the total amount of telavancin administered to the patient perday does not exceed a specified amount based on the patient's weight andcreatinine clearance. Additionally, for those patients having acreatinine clearance less than about 30 mL/minute, acute kidney injuryand mortality are also predicted to be reduced if the present dose oftelavancin is administered every 24 hours instead of every 48 hours asis recommended for the prior dose. Surprisingly, by using the dosingregimens of the present invention, retrospective analyses predict thatthe efficacy of telavancin will be maintained and the overall incidenceof acute kidney injury and mortality will be reduced.

Accordingly, in one aspect, the present invention provides a once-dailydose of telavancin for administration to a human patient havingbacteremia, pneumonia, endocarditis, osteomyelitis, or a prostheticjoint infection caused by Staphylococcus aureus, the dose comprisingtelavancin or a pharmaceutically-acceptable salt thereof in an amountselected from:

(a) about 7.5 mg/kg of telavancin (free base equivalents) if the patienthas a creatinine clearance greater than about 50 mL/minute, providedthat the total dose does not exceed about 750 mg/day;

(b) about 5.6 mg/kg of telavancin (free base equivalents) if the patienthas a creatinine clearance between about 30 mL/minute and about 50mL/minute, provided that the total dose does not exceed about 560mg/day; and

(c) about 3.8 mg/kg of telavancin (free base equivalents) if the patienthas a creatinine clearance less than about 30 mL/minute, provided thatthe total dose does not exceed about 380 mg/day.

In another aspect, the present invention provides a method foradministering telavancin to a human patient having bacteremia,pneumonia, endocarditis, osteomyelitis, or a prosthetic joint infectioncaused by Staphylococcus aureus, the method comprising administering adose of telavancin or a pharmaceutically-acceptable salt thereof to thepatient about once every 24 hours; wherein the dose of telavancinadministered to the patient is selected from:

(a) about 7.5 mg/kg of telavancin (free base equivalents) if the patienthas a creatinine clearance greater than about 50 mL/minute, providedthat the total dose does not exceed about 750 mg/day;

(b) about 5.6 mg/kg of telavancin (free base equivalents) if the patienthas a creatinine clearance between about 30 mL/minute and about 50mL/minute, provided that the total dose does not exceed about 560mg/day; and

(c) about 3.8 mg/kg of telavancin (free base equivalents) if the patienthas a creatinine clearance less than about 30 mL/minute, provided thatthe total dose does not exceed about 380 mg/day.

In yet another aspect, the present invention provides a method fortreating bacteremia, pneumonia, endocarditis, osteomyelitis, or aprosthetic joint infection caused by Staphylococcus aureus in a humanpatient, the method comprising administering a dose of telavancin or apharmaceutically-acceptable salt thereof to the patient about once every24 hours; wherein the dose of telavancin administered to the patient isselected from:

(a) about 7.5 mg/kg of telavancin (free base equivalents) if the patienthas a creatinine clearance greater than about 50 mL/minute, providedthat the total dose does not exceed about 750 mg/day;

(b) about 5.6 mg/kg of telavancin (free base equivalents) if the patienthas a creatinine clearance between about 30 mL/minute and about 50mL/minute, provided that the total dose does not exceed about 560mg/day; and

(c) about 3.8 mg/kg of telavancin (free base equivalents) if the patienthas a creatinine clearance less than about 30 mL/minute, provided thatthe total dose does not exceed about 380 mg/day.

In separate and distinct embodiments for each of these doses andmethods, in one embodiment, the patient has a creatinine clearancegreater than about 50 mL/minute. In one embodiment, the patient has acreatinine clearance between about 30 mL/minute and about 50 mL/minute.In one embodiment, the patient has a creatinine clearance less thanabout 30 mL/minute. And in one embodiment, the patient has a creatinineclearance between about 10 mL/minute and less than about 30 mL/minute.

In one embodiment, the patient has bacteremia. In one embodiment, thedose is administered for about 4 to about 6 weeks.

In one embodiment, the patient has pneumonia. In one embodiment, thedose is administered for about 7 to about 14 days.

In one embodiment, the patient has endocarditis. In one embodiment, thedose is administered for about 4 to about 6 weeks.

In one embodiment, the patient has osteomyelitis. In one embodiment, thedose is administered for about 4 to about 8 weeks.

In one embodiment, the patient has a prosthetic joint infection. In oneembodiment, the dose is administered for about 2 to about 8 weeks.

In one embodiment, the dose is administered intravenously.

In one embodiment, the Staphylococcus aureus is methicillin-resistantStaphylococcus aureus.

In one embodiment, the telavancin is administered as a hydrochloridesalt.

In one embodiment, the telavancin or a pharmaceutically-acceptable saltthereof is administered in combination with2-hydroxypropyl-β-cyclodextrin.

In another aspect, the present invention provides a once-daily dose oftelavancin for administration to a patient having a creatinine clearanceless than about 50 mL/minute and having a complicated skin and skinstructure infection caused by Staphylococcus aureus, the dose comprisingtelavancin or a pharmaceutically-acceptable salt thereof in an amountselected from:

(a) about 5.6 mg/kg of telavancin (free base equivalents) if the patienthas a creatinine clearance between about 30 mL/minute and about 50mL/minute, provided that the total dose does not exceed about 560mg/day; and

(b) about 3.8 mg/kg of telavancin (free base equivalents) if the patienthas a creatinine clearance less than about 30 mL/minute, provided thatthe total dose does not exceed about 380 mg/day.

In yet another aspect, the present invention provides a method foradministering telavancin to a human patient having a creatinineclearance less than about 50 mL/minute and having a complicated skin andskin structure infection caused by Staphylococcus aureus, the methodcomprising administering a dose of telavancin or apharmaceutically-acceptable salt thereof to the patient about once every24 hours; wherein the dose of telavancin administered to the patient isselected from:

(a) about 5.6 mg/kg of telavancin (free base equivalents) if the patienthas a creatinine clearance between about 30 mL/minute and about 50mL/minute, provided that the total dose does not exceed about 560mg/day; and

(b) about 3.8 mg/kg of telavancin (free base equivalents) if the patienthas a creatinine clearance less than about 30 mL/minute, provided thatthe total dose does not exceed about 380 mg/day.

In still another aspect, the present invention provides a method fortreating a complicated skin and skin structure infection caused byStaphylococcus aureus in a human patient having a creatinine clearanceless than about 50 mL/minute, the method comprising administering a doseof telavancin or a pharmaceutically-acceptable salt thereof to thepatient about once every 24 hours; wherein the dose of telavancinadministered to the patient is selected from:

(a) about 5.6 mg/kg of telavancin (free base equivalents) if the patienthas a creatinine clearance between about 30 mL/minute and about 50mL/minute, provided that the total dose does not exceed about 560mg/day; and

(b) about 3.8 mg/kg of telavancin (free base equivalents) if the patienthas a creatinine clearance less than about 30 mL/minute, provided thatthe total dose does not exceed about 380 mg/day.

In separate and distinct embodiments for each of these doses andmethods, in one embodiment, the patient has a creatinine clearancebetween about 30 mL/minute and about 50 mL/minute. In one embodiment,the patient has a creatinine clearance less than about 30 mL/minute. Inone embodiment, the patient has a creatinine clearance between about 10mL/minute and less than about 30 mL/minute.

In one embodiment, the dose is administered for about 7 to about 14days.

In one embodiment, the dose is administered intravenously.

In one embodiment, the Staphylococcus aureus is methicillin-resistantStaphylococcus aureus.

In one embodiment, the telavancin is administered as a hydrochloridesalt.

In one embodiment, telavancin or a pharmaceutically-acceptable saltthereof is administered in combination with2-hydroxypropyl-β-cyclodextrin.

In another aspect, the present invention provides a once-daily dose oftelavancin for administration to a human patient having an infectioncaused by Staphylococcus aureus, the dose comprising an amount oftelavancin (free base equivalents) in the range defined by formula (I):

Dose(mg)=AUC_(target)*1.15*(WT/77)^(0.352)*(CrCl/99)^(0.454)±5.0  (I)

wherein:

AUC_(target) is a target area under the concentration curve selectedfrom the range of about 220 to about 730 μg*hr/mL;

WT is the weight of the patient in kilograms; and

CrCl is the creatinine clearance of the patient in mL/minute.

In yet another aspect, the present invention provides a method foradministering telavancin to a human patient having an infection causedby Staphylococcus aureus, the method comprising administering a dose oftelavancin or a pharmaceutically-acceptable salt thereof to the patientabout once every 24 hours; wherein the dose comprises an amount oftelavancin (free base equivalents) in the range defined by formula (I).

In still another aspect, the present invention provides a method fortreating an infection caused by Staphylococcus aureus in a humanpatient, the method comprising administering a dose of telavancin or apharmaceutically-acceptable salt thereof to the patient about once every24 hours; wherein the dose comprises an amount of telavancin (free baseequivalents) in the range defined by formula (I).

In another aspect, the present invention provides a once-daily dose oftelavancin for administration to a human patient having an infectioncaused by Staphylococcus aureus, the dose comprising an amount oftelavancin (free base equivalents) selected from a nomogram wherein eachvalue in the nomogram is in the range defined by formula (I).

In yet another aspect, the present invention provides a method foradministering telavancin to a human patient having an infection causedby Staphylococcus aureus, the method comprising administering a dose oftelavancin or a pharmaceutically-acceptable salt thereof to the patientabout once every 24 hours; wherein the dose comprises an amount oftelavancin (free base equivalents) selected from a nomogram wherein eachvalue in the nomogram is in the range defined by formula (I).

In still another aspect, the present invention provides a method fortreating an infection caused by Staphylococcus aureus in a humanpatient, the method comprising administering a dose of telavancin or apharmaceutically-acceptable salt thereof to the patient about once every24 hours; wherein the dose comprises an amount of telavancin (free baseequivalents) selected from a nomogram wherein each value in the nomogramis in the range defined by formula (I).

In separate and distinct embodiments for each of these doses andmethods, in one embodiment, the once-daily dose defined by formula (I)is rounded to the nearest 10 mg.

In one embodiment, the AUC_(target) is 600 μg*hr/mL.

In one embodiment, the patient has bacteremia. In one embodiment, thedose is administered for about 4 to about 6 weeks.

In one embodiment, the patient has pneumonia. In one embodiment, thedose is administered for about 7 to about 14 days.

In one embodiment, the patient has endocarditis. In one embodiment, thedose is administered for about 4 to about 6 weeks.

In one embodiment, the patient has osteomyelitis. In one embodiment, thedose is administered for about 4 to about 8 weeks.

In one embodiment, the patient has a prosthetic joint infection. In oneembodiment, the dose is administered for about 2 to about 8 weeks.

In one embodiment, the patient has a complicated skin and skin structureinfection. In one embodiment, the dose is administered for about 7 toabout 14 days.

In one embodiment, the dose is administered intravenously.

In one embodiment, the Staphylococcus aureus is methicillin-resistantStaphylococcus aureus.

In one embodiment, the telavancin is administered as a hydrochloridesalt.

In one embodiment, the telavancin or a pharmaceutically-acceptable saltthereof is administered in combination with2-hydroxypropyl-β-cyclodextrin.

In another aspect, the present invention provides a once-daily dose oftelavancin for administration to a human patient having an infectioncaused by Staphylococcus aureus, the dose comprising an amount oftelavancin (free base equivalents) selected from a nomogram comprisingthe values:

CrCl mg 10 20 30 40 50 70 90 120 150 WT 50 210 290 340 390 430 510 570650 720 60 220 310 370 420 460 540 610 690 760 70 240 320 390 440 490570 640 730 810 90 260 350 420 480 530 620 700 800 880 110 280 380 450520 570 670 750 850 940 130 290 400 480 550 610 710 790 910 1000 150 310420 510 580 640 750 840 950 1050wherein:

WT is the weight of the patient in kilograms (rounded to the nearestvalue in the nomogram); and

CrCl is the creatinine clearance of the patient in mL/minute (rounded tothe nearest value in the nomogram).

In yet another aspect, the present invention provides a method foradministering telavancin to a human patient having an infection causedby Staphylococcus aureus, the method comprising administering a dose oftelavancin or a pharmaceutically-acceptable salt thereof to the patientabout once every 24 hours; wherein the dose comprises an amount oftelavancin (free base equivalents) selected from the nomogram above.

In still another aspect, the present invention provides a method fortreating an infection caused by Staphylococcus aureus in a humanpatient, the method comprising administering a dose of telavancin or apharmaceutically-acceptable salt thereof to the patient about once every24 hours; wherein the dose comprises an amount of telavancin (free baseequivalents) selected from the nomogram above.

In separate and distinct embodiments for each of these doses andmethods, in one embodiment, the patient has bacteremia. In oneembodiment, the dose is administered for about 4 to about 6 weeks.

In one embodiment, the patient has pneumonia. In one embodiment, thedose is administered for about 7 to about 14 days.

In one embodiment, the patient has endocarditis. In one embodiment, thedose is administered for about 4 to about 6 weeks.

In one embodiment, the patient has osteomyelitis. In one embodiment, thedose is administered for about 4 to about 8 weeks.

In one embodiment, the patient has a prosthetic joint infection. In oneembodiment, the dose is administered for about 2 to about 8 weeks.

In one embodiment, the patient has a complicated skin and skin structureinfection. In one embodiment, the dose is administered for about 7 toabout 14 days.

In one embodiment, the dose is administered intravenously.

In one embodiment, the Staphylococcus aureus is methicillin-resistantStaphylococcus aureus.

In one embodiment, the telavancin is administered as a hydrochloridesalt.

In one embodiment, the telavancin or a pharmaceutically-acceptable saltthereof is administered in combination with2-hydroxypropyl-β-cyclodextrin.

Other aspects and embodiments of this invention are disclosed herein.

BRIEF DESCRIPTION OF THE DRAWINGS

Various aspects of the present invention are illustrated by reference tothe accompanying drawings.

FIG. 1 shows the predicted AUC_(0-24h) of the prior dosing regimen as afunction of weight.

FIG. 2 shows the predicted AUC_(0-24h) of the prior dosing regimen as afunction of renal impairment.

In FIG. 1 and FIG. 2, the black point indicates the median, the top andbottom of the box indicate the lower and upper quartiles (25% and 75%),the whiskers indicate the upper and lower data within 1.5 times theinterquartile range, and the box width indicates the number of subjectsin each category (there were no outliers).

FIG. 3A shows the distribution of predicted AUC_(0-24h) values for allcSSSI and HABP/VABP subjects dosed with the prior dosing regimen.

FIG. 3B shows the distribution of predicted AUC_(0-24h) values for allcSSSI and HABP/VABP subjects dosed with a new dosing regimen of thepresent invention.

FIG. 4A shows the distribution of the predicted AUC_(0-24h) values forHABP/VABP subjects with a CrCl<30 mL/min with the prior dosing regimen(10 mg/kg Q48h).

FIG. 4B shows the distribution of the predicted AUC_(0-24h) values forHABP/VABP subjects with a CrCl<30 mL/min with a daily dosing regimen (5mg/kg QD).

FIG. 4C shows the distribution of the predicted AUC_(0-24h) values forHABP/VABP subjects with a CrCl<30 mL/min with a new dosing regimen (3.75mg/kg QD with a maximum dose of 375 mg for subjects >100 kg) of thepresent invention.

FIG. 5A shows a comparison of predicted exposures (AUC) for varioussubject weight ranges for the prior dosing regimen and a new dosingregimen of the present invention.

FIG. 5B shows a comparison of predicted exposures (AUC) for varioussubject renal function ranges for the prior dosing regimen and a newdosing regimen of the present invention.

FIG. 6A shows the observed versus predicted telavancin concentrationsfor normal subjects.

FIG. 6B shows the observed versus predicted telavancin concentrationsfor pre-obese subjects.

FIG. 6C shows the observed versus predicted telavancin concentrationsfor obese Class I subjects.

FIG. 6D shows the observed versus predicted telavancin concentrationsfor obese Class II subjects.

FIG. 6E shows the observed versus predicted telavancin concentrationsfor obese Class III subjects.

FIG. 7A shows the weighted residual versus population predictedtelavancin concentrations for normal subjects.

FIG. 7B shows the weighted residual versus population predictedtelavancin concentrations for pre-obese subjects.

FIG. 7C shows the weighted residual versus population predictedtelavancin concentrations for Class I obese subjects.

FIG. 7D shows the weighted residual versus population predictedtelavancin concentrations for Class II obese subjects.

FIG. 7E shows the weighted residual versus population predictedtelavancin concentrations for Class III obese subjects.

FIG. 8A is a scatter plot of the predicted telavancin AUC_(0-24h) versusBMI.

FIG. 8B is a scatter plot of the predicted telavancin C_(max) versusBMI.

FIG. 9 shows predicted telavancin total exposure (AUC_(0-24h)) byobesity category.

FIG. 10 shows predicted telavancin maximum exposure (C_(max)) by obesitycategory.

FIG. 11A shows a plot of individually predicted exposure versus observedconcentration (μg/mL) for all Phase 3 subjects where PK samples werecollected (n=579).

FIG. 11B shows a plot of for individually predicted exposure versusobserved exposure (AUC_(0-24h)) for all Phase 3 subjects where PKsamples were collected (n=579).

FIG. 12A shows a plot of individually predicted exposure versus measuredexposure (AUC_(0-24h)) for all HABP/VABP subjects where PK samples werecollected.

FIG. 12B shows a plot of individually predicted exposure versus measuredexposure (AUC_(0-24h)) for all cSSSI subjects where PK samples werecollected.

FIG. 13A shows logistic regression fit for 28-day all-cause mortality asa function of exposure (AUC_(0-24h)) for all Phase 3 subjects where PKsamples were collected (n=579).

FIG. 13B shows logistic regression fit for AKI as a function of exposure(AUC_(0-24h)) for all Phase 3 subjects where PK samples were collected(n=579).

FIG. 13C shows logistic regression fit for clinical response at TOC as afunction of exposure (AUC_(0-24h)) for all Phase 3 subjects where PKsamples were collected (n=579).

FIG. 14A shows logistic regression fit for 28-day all-cause mortality asa function of exposure (AUC_(0-24h)) for all Phase 3 HABP/VABP subjectswhere PK samples were collected (n=196).

FIG. 14B shows logistic regression fit for AKI as a function of exposure(AUC_(0-24h)) for all Phase 3 HABP/VABP subjects where PK samples werecollected (n=196).

FIG. 14C shows logistic regression fit for clinical response at TOC as afunction of exposure (AUC_(0-24h)) for all Phase 3 HABP/VABP subjectswhere PK samples were collected (n=196).

FIG. 15A shows logistic regression fit for 28-day all-cause mortality asa function of exposure (AUC_(0-24h)) for HABP/VABP subjects with renalimpairment (CrCl≦50 mL/min) where PK samples were collected.

FIG. 15B shows logistic regression fit for 28-day all-cause mortality asa function of exposure (AUC_(0-24h)) for HABP/VABP subjects withoutrenal impairment (CrCl>50 mL/min) where PK samples were collected.

FIG. 16A shows logistic regression fit for AKI as a function of exposure(AUC_(0-24h)) for all Phase 3 cSSSI subjects where PK samples werecollected (n=383).

FIG. 16B shows logistic regression fit for clinical response at TOC as afunction of exposure (AUC_(0-24h)) for all Phase 3 cSSSI subjects wherePK samples were collected (n=383).

FIG. 17A shows logistic regression fit for AKI as a function of exposure(AUC_(0-24h)) for all Phase 3 cSSSI subjects below 100 kg where PKsamples were collected.

FIG. 17B shows logistic regression fit for AKI as a function of exposure(AUC_(0-24h)) for all Phase 3 cSSSI subjects above 100 kg where PKsamples were collected.

FIG. 18 shows a comparison of predicted exposures (AUC) for varioussubject weight ranges for the prior dosing regimen and a new dosingregimen of the present invention based on formula (i).

FIG. 19 shows a comparison of predicted exposures (AUC) for varioussubject renal function ranges for the prior dosing regimen and a newdosing regimen of the present invention based on formula (i).

DETAILED DESCRIPTION OF THE INVENTION

Amongst various aspects and embodiments, the present invention providesdoses and methods for administering telavancin or apharmaceutically-acceptable salt thereof and methods for treating aninfection caused by Staphylococcus aureus, such as bacteremia,pneumonia, endocarditis, osteomyelitis, a prosthetic joint infection ora complicated skin and skin structure infection, in a human patientusing telavancin or a pharmaceutically-acceptable salt thereof.

DEFINITIONS

When describing this invention, the following terms have the followingmeanings unless otherwise indicated.

The term “free base equivalent(s)” means the amount of free base in anacid addition salt of the free base and an acid (i.e., the amount offree base if the acid addition salt form was converted to the free baseform). For example, one gram of telavancin dihydrochloride salt(MW=1828.5) contains 0.96 grams of telavancin (MW=1755.63) and 0.04grams of hydrogen chloride (MW=36.46); or 0.96 grams of telavancin freebase equivalents.

The term “pharmaceutically-acceptable salt” means a salt that isacceptable for administration to a human patient (e.g., salts havingacceptable mammalian safety for a given dosage regime). Representativepharmaceutically-acceptable salts of telavancin include acid additionsalts of telavancin with acetic, ascorbic, benzenesulfonic, benzoic,camphorsulfonic, citric, ethanesulfonic, edisylic, fumaric, gentisic,gluconic, glucoronic, glutamic, hippuric, hydrobromic, hydrochloric,isethionic, lactic, lactobionic, maleic, malic, mandelic,methanesulfonic, mucic, naphthalenesulfonic, naphthalene-1,5-disulfonic,naphthalene-2,6-disulfonic, nicotinic, nitric, orotic, pamoic,pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonicand xinafoic acid, and the like.

The term “present dose” or “present dosing regimen” or “new dose” or“new dosing regimen” refers to a dose or dosing regimen of the presentinvention.

The term “prior dose” or “prior dosing regimen” refers to an existing orprior art dose or dosing regimen, such as the dosing regimen set forthin the VIBATIV® (telavancin) Prescribing Information; Revised March2014.

The term “telavancin” means the compoundN^(3″)-[2-(decylamino)ethyl]-29-[[(phosphonomethyl)amino]methyl]vancomycinhaving the formula:

The term “telavancin hydrochloride” means any hydrochloride salt oftelavancin, including, for example, the mono-, di- and trihydrochloridesalts of telavancin and mixtures thereof (e.g., x.HCl, where x is 1 to3).

In one embodiment, the present invention is based, in part, on thediscovery that rates of acute kidney injury and mortality are predictedto be reduced and antibacterial efficacy is predicted to be maintainedif:

(i) the dose of telavancin administered to a patient is about 25 percentlower than the currently recommended dose based on the patient'screatinine clearance;

(ii) the total amount of telavancin administered to a patient per daydoes not exceed a specified amount based on the patient's creatinineclearance; and

(iii) for those patients having a creatinine clearance less than about30 mL/minute, rates of acute kidney injury and mortality are predictedto be reduced if the dose of telavancin is administered every 24 hoursinstead of every 48 hours as is currently recommended.

This discovery is based, in part, on retrospective analyses of the Phase3 clinical studies for telavancin for cSSSI and HABP/VABP. Based onthese analyses, higher exposures to telavancin were found to beassociated with a higher probability of mortality in HABP/VABP subjectswith moderate or severe impairment in renal function and a higherlikelihood of AKI in cSSSI subjects. However, for all HABP/VABP andcSSSI subjects, no relationship between exposure and clinical responseat test of cure was identified. This is likely due to the range ofexposures being sufficiently high so as not to compromise clinicalefficacy. Based on these exposure-response analyses, the doses of thepresent invention are expected to reduce the risk of acute kidney injuryin all patients and mortality in patients with moderate to severe renalimpairment while not affecting efficacy.

Additionally, analyses of the clinical data have shown a goodcorrelation between the pharmacokinetics of telavancin with the weightand creatinine clearance of the patients. This correlation provides aformula for determining a once-daily dose of telavancin based on atarget AUC and the patient's weight and creatinine clearance.Accordingly, in another embodiment, the present invention is based, inpart, on the discovery that rates of acute kidney injury and mortalityare predicted to be reduced and antibacterial efficacy is predicted tobe maintained if the dose of telavancin (free base equivalents) is basedon formula (i):

Dose(mg)=AUC_(target)*1.15*(WT/77)^(0.352)*(CrCl/99)^(0.454)  (i)

where:

AUC_(target) is the target area under the concentration curve inμg*hr/mL;

WT is the weight of the patient in kilograms; and

CrCl is the creatinine clearance of the patient in mL/minute.

In one embodiment, the dose determined by formula (i) is a range of ±5mg of the dose amount calculated by formula (i). In another embodiment,the dose determined by formula (i) is rounded to the nearest 10 mg.

In another embodiment, formula (i) is used to create a nomogram orlook-up-table to quickly determine the appropriate dose for a targetedAUC based on the patient's weight and creatinine clearance. In oneembodiment, the dose determined by the formula is rounded to the nearest10 mg when used in the nomogram.

Telavancin Drug Substance

Telavancin or any pharmaceutically-acceptable salt of telavancin can beemployed in this invention. In one embodiment, telavancin hydrochlorideis used. Telavancin hydrochloride is an off-white to slightly coloredamorphous powder with the empirical formula C₈₀H₁₀₆C₁₂N₁₁O₂₇P.xHCl(where x=1 to 3). In a particular embodiment, telavancin dihydrochlorideis used.

Telavancin and telavancin hydrochloride salts can be prepared by methodsand processes known in the art. See, for example, U.S. Pat. Nos.6,635,618 B2; 6,872,701 B2; 6,887,976 B2; 6,979,723 B2; 7,015,305 B2;7,015,307 B2; 7,074,890 B2; 7,160,984 B2; 7,208,471 B2; 7,301,004 B2;7,375,181 B2; 7,468,420 B2; 7,531,623 B2; 7,858,583 B2; 8,003,755 B2;and 8,093,354 B2.

Telavancin Drug Product

Telavancin is typically employed in this invention as a pharmaceuticalcomposition comprising telavancin or a pharmaceutically-acceptable saltthereof and one or more excipients or carriers. Any suitable excipientsor carriers may be used. In one embodiment, the pharmaceuticalcomposition is a storage-stable formulation suitable for reconstitutionprior to administration to the patient.

For example, telavancin hydrochloride is commercially-available underthe trademark VIBATIV® (telavancin) as a sterile, preservative-free,white to slightly colored lyophilized powder containing telavancinhydrochloride, 2-hydroxypropyl-β-cyclodextrin and mannitol. The productis available in single-use 250 mg and 750 mg strength vials. The 250 mgstrength vial contains telavancin hydrochloride (equivalent to 250 mg oftelavancin as the free base); 2500 mg of 2-hydroxypropyl-β-cyclodextrin(Hydroxypropylbetadex, Ph. Eur.); and 312.5 mg of mannitol. The 750 mgstrength vial contains telavancin hydrochloride (equivalent to 750 mg oftelavancin as the free base); 7500 mg of 2-hydroxypropyl-β-cyclodextrin(Hydroxypropylbetadex, Ph. Eur.); and 937.5 mg of mannitol. Whenreconstituted, these pharmaceutical compositions form a clear toslightly colored solution with a pH of about 4.5±0.5.

Determination of the Dose

The dose of telavancin to be administered to a patient is determinedbased on the body weight and creatinine clearance of the patient; and insome embodiments, by the target AUC.

The patient's body weight is determined using any conventional means formeasuring weight such as a scale. For example, a patient's body weightcan be determined using a built-in bed scale, a wheel-chair scale, adigital standing scale, a mechanical standing scale and the like.Representative patient body weights are typically in the range of fromabout 30 to about 320 kg.

The patient's creatinine clearance (CrCl) is typically estimated usingthe Cockcroft-Gault formula:

${CrCl} = {\frac{\left\lbrack {140 - {{age}\mspace{14mu} ({years})}} \right\rbrack \times {ideal}\mspace{14mu} {body}\mspace{14mu} {weight}\mspace{14mu} ({kg})^{*}}{\left\lbrack {72 \times {serum}\mspace{14mu} {creatinine}\mspace{14mu} \left( {{mg}\text{/}{dL}} \right)} \right\rbrack}\left\{ {\times 0.85\mspace{14mu} {for}\mspace{14mu} {female}\mspace{14mu} {patients}} \right\}}$ ^(*)Use  actual  body  weight  if < ideal  body  weight

See, e.g., Cockcroft et al., Nephron. 1976, 16(1), 31-41.

The patient's ideal body weight is typically determined using the Devineformula:

IBW(male)=50 kg+0.9 kg/cm over 152 cm in height

IBW(female)=45.5 kg+0.9 kg/cm over 152 cm in height

As noted in the Cockcroft-Gault formula, if the patient's actual bodyweight is less than the ideal body weight, then the actual body weightis used in the formula.

A patient's serum creatinine is determined using any conventional bloodtest for measuring serum creatinine, such as those described in Israni AK, Kasiske B L. Laboratory assessment of kidney disease: filtrationrate, urinalysis, and proteinuria. In: Taal M W, Chertow G M, Marsden PA, et al., eds. Brenner and Rector's The Kidney. 9th ed. Philadelphia,Pa.: Elsevier Saunders; 2011:chap 25.

Representative patient creatinine clearance values are typically in therange of from about 3 to about 200 mL/minute; including about 3 to about150 mL/minute.

In one embodiment, once the patient's body weight and creatinineclearance are determined, the daily dose of telavancin for the patientis determined as shown in Table I:

TABLE I Dose of Telavancin Based on Creatinine Clearance and Body WeightCreatinine Clearance Dose of Telavancin Not to Exceed mL/min mg/kgmg/day >50 7.5 750 30-50 5.6 560 <30 3.8 380

In one embodiment, >50 mL/minute includes the range about 50 mL/minuteto about 200 mL/minute. In one embodiment, <30 mL/minute includes therange about 10 mL/minute to less than about 30 mL/minute.

For example, a patient having a creatinine clearance of about 100 mL/minand a body weight of about 70 kg would be given a daily dose oftelavancin (free base equivalents) of about 525 mg (i.e., 70 kg×7.5mg/kg=525 mg). Another patient having a creatinine clearance of about 40mL/min and a body weight of about 70 kg would be given a daily dose oftelavancin (free base equivalents) of about 392 mg (i.e., 70 kg×5.6mg/kg=392 mg). And yet another patient having a creatinine clearance ofabout 20 mL/min and a body weight of about 70 kg would be given a dailydose of telavancin (free base equivalents) of about 266 mg (i.e., 70kg×3.8 mg/kg=266 mg).

In this embodiment, for patients having a body weight greater than 100kg, the daily dose of telavancin (free base equivalents) is capped at aspecified amount based on the patient's creatinine clearance. Forpatients having a creatinine clearance greater than 50 mL/min, themaximum daily dose of telavancin is 750 mg. For patients having acreatinine clearance of 30 to 50 mL/min, the maximum daily dose oftelavancin is 560 mg; and for patients having a creatinine clearanceless than 30 mL/min, the maximum daily dose of telavancin is 380 mg.

For example, a patient having a creatinine clearance of about 100 mL/minand a body weight of about 120 kg would be given a daily dose oftelavancin (free base equivalents) of about 750 mg, since the dosecalculated based on the patient's body weight exceeds 750 mg (i.e., 120kg×7.5 mg/kg=900 mg). Another patient having a creatinine clearance ofabout 40 mL/min and a body weight of about 120 kg would be given a dailydose of telavancin (free base equivalents) of about 560 mg, since thedose calculated based on the patient's body weight exceeds 560 mg (i.e.,120 kg×5.60 mg/kg =672 mg). And yet another patient having a creatinineclearance of about 20 mL/min and a body weight of about 120 kg would begiven a daily dose of telavancin (free base equivalents) of about 380mg, since the dose calculated based on the patient's body weight exceeds380 mg (i.e., 120 kg×3.80 mg/kg=456 mg).

In another embodiment, the daily dose of telavancin for the patient isdetermined using formula (I):

Dose(mg)=AUC_(target)*1.15*(WT/77)^(0.352)*(CrCl/99)^(0.454)±5.0  (I)

wherein:

AUC_(target) is a target area under the concentration curve selectedfrom the range of about 220 to about 730 μg*hr/mL;

WT is the weight of the patient in kilograms; and

CrCl is the creatinine clearance of the patient in mL/minute.

The AUC_(target) is typically determined by the physician treating thepatient. In one embodiment, the AUC_(target) is selected from the rangeof about 220 to about 730 μg*hr/mL. In another embodiment, theAUC_(target) is selected from the range of about 450 to about 730μg*hr/mL; including about 550 to about 700 μg*hr/mL. In anotherembodiment, the AUC_(target) is selected from 450, 460, 470, 480, 490,500, 510, 520, 530, 540, 550, 560, 570, 580, 590, 600, 610, 620, 630,640, 650, 660, 670, 680, 690, 700, 710, 720 and 730; including 550, 600,650 and 700 μg*hr/mL. In a particular embodiment, the AUC_(target) is i600 μg*hr/mL.

Formula (I) provides a simple and accurate way for a physician todetermine a personalized dose of telavanin (free base equivalents) basedon the patient's weight and creatinine clearance. For example, usingformula (I) and an AUC_(target) of 600 μg*hr/mL, a patient having acreatinine clearance of about 100 mL/min and a body weight of about 70kg would be given a daily dose of telavancin (free base equivalents) ofabout 667.2±5 mg; or rounded to the nearest 10 mg, about 670 mg. Anotherpatient having a creatinine clearance of about 40 mL/min and a bodyweight of about 70 kg would be given a daily dose of telavancin (freebase equivalents) of about 442.4±5 mg; or rounded to the nearest 10 mg,about 440 mg. And yet another patient having a creatinine clearance ofabout 20 mL/min and a body weight of about 70 kg would be given a dailydose of telavancin (free base equivalents) of about 322.9±5 mg; orrounded to the nearest 10 mg, about 320 mg.

In another embodiment, the daily dose of telavancin for the patient isdetermined by selecting the dose from a nomogram or look-up-tablewherein each value in the nomogram is in the range defined by formula(I). For example, to prepare a nomogram using formula (I), anAUC_(target) is selected, such as 600 μg*hr/mL. A table is then preparedusing formula (I) and a series of patient weights and creatinineclearance values. For example, the following patient weights can beused: 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110,115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165 and 170 kilogram;or selections thereof. Similarly, the following creatinine clearancevalues can be used: 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70,75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145,and 150 mL/minute; or selections thereof. In one embodiment, the dosevalues listed in the nomogram are rounded to the nearest 10 mg.

For example, using an AUC_(target) of 600 μg*hr/mL, the followingrepresentative nomogram was prepared using formula (I):

CrCl mg 10 20 30 40 50 70 90 120 150 WT 50 210 290 340 390 430 510 570650 720 60 220 310 370 420 460 540 610 690 760 70 240 320 390 440 490570 640 730 810 90 260 350 420 480 530 620 700 800 880 110 280 380 450520 570 670 750 850 940 130 290 400 480 550 610 710 790 910 1000 150 310420 510 580 640 750 840 950 1050wherein:

WT is the weight of the patient in kilograms (rounded to the nearestvalue in the nomogram); and

CrCl is the creatinine clearance of the patient in mL/minute (rounded tothe nearest value in the nomogram).

A nomogram provides a simple and accurate way for a physician todetermine a personalized dose of telavanin (free base equivalents) basedon the patient's weight and creatinine clearance. For example, usingthis nomogram, a patient having a creatinine clearance of about 100mL/min and a body weight of about 70 kg would be given a daily dose oftelavancin (free base equivalents) of about 640 mg. Another patienthaving a creatinine clearance of about 40 mL/min and a body weight ofabout 70 kg would be given a daily dose of telavancin (free baseequivalents) of about 440 mg. And yet another patient having acreatinine clearance of about 20 mL/min and a body weight of about 70kg, would be given a daily dose of telavancin (free base equivalents) ofabout 320 mg.

Various nomograms can be prepared using formula (i) or formula (I) andall such nomograms are included within the scope of the presentinvention.

Once a patient begins treatment with telavancin, the patient's bodyweight and creatinine clearance are typically measured periodically,such as daily or weekly, and the dose of telavancin administered to thepatient is adjusted, if necessary, using the new values to determine theproper dose of telavancin, e.g., using Table I, formula (I) or anomogram.

Preparation and Administration of the Dose

Telavancin is typically administered to the patient by reconstitutingthe telavancin drug product and then further diluting the reconstitutedmixture to form a dilute solution suitable for intravenousadministration.

For example, a 250 mg vial of telavancin drug product can bereconstituted with 15 mL of 5% Dextrose Injection; Sterile Water forInjection; or 0.9% Sodium Chloride Injection. The resultant solution hasa concentration of 15 mg/mL and total volume of about 17.0 mL.

Similarly, a 750 mg vial of telavancin drug product can be reconstitutedwith 45 mL of 5% Dextrose Injection; Sterile Water for Injection; or0.9% Sodium Chloride Injection. The resultant solution has aconcentration of 15 mg/mL and total volume of about 50.0 mL.

Once the telavancin drug product has been reconstituted (e.g., to 15 mgof telavancin (free base equivalents) per mL), the following formula canbe used to calculate the volume of reconstituted VIBATIV solutionrequired to prepare a dose:

${{Volume}\mspace{14mu} {of}\mspace{14mu} {reconstituted}\mspace{14mu} {solution}\mspace{14mu} ({mL})} = \frac{{Telavancin}\mspace{14mu} {dose}\mspace{14mu} ({mg})}{{Telavancin}\mspace{14mu} {concentration}\mspace{14mu} \left( {{mg}\text{/}{mL}} \right)}$

For example, a 750 mg dose of telavancin would require 50 mL ofreconstituted solution having a telavancin concentration of 15 mg/mL.

For doses of 150 to 750 mg, the appropriate volume of reconstitutedsolution is typically further diluted with 100 to 250 mL of an infusionsolution prior to infusion. Alternatively, doses can be further dilutedusing a volume that results in a final concentration of 0.6 to 8 mg/mL.Representative infusion solutions include, for example, 5% DextroseInjection; 0.9% Sodium Chloride Injection; Lactated Ringer's Injection;and the like.

The dosing solution is then typically administered to the patient byintravenous infusion over a period of about 60 minutes, including about45 to about 75 minutes.

Treatment of Infections Caused by Staphylococcus aureus

In one embodiment, the methods of this invention are used to treatbacteremia caused by Staphylococcus aureus, including uncomplicatedbacteremia (UCB) and complicated bacteremia (CB). In this embodiment,telavancin will typically be dosed daily for about 2 to about 6 weeks,or until the bacteremia has been treated. In a particular embodiment,telavancin is dosed daily for about 4 to about 6 weeks.

In another embodiment, the methods of this invention are used to treatpneumonia caused by Staphylococcus aureus, including hospital-acquiredbacterial pneumonia (HABP) and ventilator-associated bacterial pneumonia(VABP). In this embodiment, telavancin will typically be dosed daily forabout 7 to about 14 days, or until the pneumonia has been treated.

In another embodiment, the methods of this invention are used to treatendocarditis caused by Staphylococcus aureus. In this embodiment,telavancin will typically be dosed daily for about 4 to about 6 weeks,or until the endocarditis has been treated.

In another embodiment, the methods of this invention are used to treatosteomyelitis caused by Staphylococcus aureus. In this embodiment,telavancin will typically be dosed daily for about 4 to about 8 weeks,or until the osteomyelitis has been treated. In one embodiment,treatment is for at least 6 weeks.

In another embodiment, the methods of this invention are used to treat aprosthetic joint infection (PJI) caused by Staphylococcus aureus. Inthis embodiment, telavancin will typically be dosed daily for about 2 toabout 8 weeks, including about 4 to about 6 weeks, or until theosteomyelitis has been treated. In one embodiment, treatment is for atleast 6 weeks.

In another embodiment, the methods of this invention are used to treat acomplicated skin and skin structure infection caused by Staphylococcusaureus. In this embodiment, telavancin will typically be dosed daily forabout 7 to about 14 days, or until the complicated skin and skinstructure infection has been treated.

The methods of the present invention can be used to treat infectionscaused by methicillin-susceptible Staphylococcus aureus andmethicillin-resistant Staphylococcus aureus. Identification ofStaphylococcus aureus, including the particular strain of Staphylococcusaureus, as the causative agent of an infection can be achieved usingconventional diagnostic tests, including rapid diagnostic tests. Forexample, Staphylococcus aureus bacteremia can be identified using ablood culture test, Staphylococcus aureus pneumonia can be identifiedusing a sputum, blood or pleural fluid culture, and a Staphylococcusaureus complicated skin and skin structure infection can be identifiedusing a skin, wound or fluid sample from the site of the infection.

Use of a daily dosing regimen of the present invention to treatinfections caused by Staphylococcus aureus is expected to provide asimilar clinical response at test of cure (TOC) relative to the priordosing regimen with a predicted reduction in the risk of AKI and apredicted reduction in 28-day-all-cause mortality as described in thefollowing Examples.

EXAMPLES

The following examples are provided to illustrate various representativeembodiments and aspects of this invention and are not intended to limitthe scope of this invention unless specifically indicated.

The following abbreviations are used herein:

Abbreviation Definition ε (ERR) Independent normally distributed randomeffects with mean zero and variance σ² θ (THETA) Typical (population)value of a pharmacokinetic parameter (theta) σ² Variance ofintra-individual error (ε) ω² Variance of inter-individual error (η) η(ETA) Independent normally distributed random effects with mean zero andvariance ω² AUC Area under the concentration-time curve BLQ Below thelimit of quantitation for the bioanalytical assay BMI Body mass index(kg/m²) CI Confidence interval CL Clearance (L/hr) Cl/F Oral clearance(L/h) CrCl Creatinine clearance (mL/min) cm Centimeter(s) C_(max)Maximum observed concentration CWRES Conditional weighted residuals DVDependent variable (observed concentration) F Bioavailability fractionFOCE INTER First order conditional estimation with interaction g Gram(s)hr Hour HT Height in cm in Inch(es) IPRED Predicted values for theindividual KA Absorption rate constant (per h) Ke Elimination rateconstant (per h) kg Kilogram(s) L Liter LLOQ Lower limit of quantitationLOESS Local regression MDV Missing dependent variable (concentration)min Minute mL Milliliter mg Milligram(s) NONMEM Nonlinear mixed effectsmodeling software PK Pharmacokinetic PRED Predicted values for thepopulation PRED Predicted values for the population Q/FIntercompartmental clearance R Software program for data handling,plotting and modeling RES Residuals; differences between observed andpredicted values RSE Relative standard error SD Standard deviation SEStandard error SeCr Serum creatinine (mg/dL) t_(1/2) Half-life (hours)Vc/F Volume of distribution of the central compartment Vp/F Volume ofdistribution of the peripheral compartment WRES Weighted residuals WHOWorld Health Organization WT Weight in kg

Other abbreviations used herein have their standard meanings unlessotherwise indicated.

Example 1 Simulations of Pharmacokinetic Exposure to Telavancin inSubjects with the Prior Dosing Regimen and a New Dosing Regimen 1.1Summary

The objective of this analysis was to estimate the exposure totelavancin from the prior dosing regimen (10 mg/kg QD) and a new dosingregimen (7.5 mg/kg QD) in subjects with normal renal function andvarious stages of renal impairment. Exposures from a QD dose forsubjects with CrCl<30 mL/min, a dose reduction of 25% (relative to theprior 10 mg/kg dose) and a maximum dose cap of 750 mg (or 562 mg forthose with moderate renal impairment or 375 mg for those with severerenal impairment) for subjects exceeding 100 kg were compared toestimated exposures from the prior doses, e.g., the doses recommended inVIBATIV® (telavancin) Prescribing Information; Revised March 2014.

Exposures were based on 100 simulated clinical trials using theall-treated telavancin population (n=1771 subjects) from the existingPhase III HAP (n=750) and cSSSI (n=1021) study data and demographics.

In this analysis, the new dosing regimen maintains a comparable range ofexposures for all subjects with a predicted 23% reduction in28-day-all-cause mortality, a 37% reduction in the risk of AKI, and apredicted similar clinical response at TOC relative to the prior 10mg/kg QD dose.

1.2 Introduction

Telavancin is a concentration dependent, rapidly bactericidal,injectable antibiotic with activity against clinically important Grampositive pathogens. The drug is approved in the US for treatment ofcomplicated skin and skin structure infections (cSSSI) and hospitalacquired bacterial pneumonia/ventilator acquired bacterial pneumonia(HABP/VABP) in adults.

Exposures for a new dosing regimen for telavancin were estimated using apopulation PK model developed from Phase 1, 2 and 3 clinical studies.Alterations in the dosing regimen from the prior dosing regimen were:(1) dose reduced by 25% in all subjects, (2) maximum dose limited to thedose administered for subjects at 100 kg and (3) halve the dose andincrease dose frequency to QD for subjects with CrCl<30 mL/min.

Telavancin is primarily cleared via the kidneys and is dosed based onweight. The prior telavancin dosing regimen adjusts the dose in renallyimpaired subjects to maintain comparable exposures. No additional doseadjustments are recommended for obesity, but population PK analysis haspredicted that subjects with increased BMI have higher exposures (seeExample 2).

Prospective analysis of telavancin Phase 3 data has suggested increasedexposures are associated with an increased probability of AKI in allsubjects, and an increased likelihood of mortality in HABP/VABP subjectswith renal impairment (see Example 3). No relationship was identifiedbetween exposure and efficacy (e.g., clinical response at test of cure).

A new dosing regimen was evaluated in simulated patients that aimed tooptimize exposures in all subjects and maintain comparable exposures insubjects with increased weight or decreased renal function relative topatients with normal weight and/or normal renal function. Telavancinexposures for this new dosing regimen were estimated by generating avirtual population of HABP/VABP and cSSSI subjects (n=1771) using thedemographics of the all-treated population in the Phase 3 trials.Steady-state exposures were estimated based on a total of 100simulations following the administration of telavancin. The predictedlikelihood of mortality, AKI and efficacy for each simulation wasestimated using a logistic regression model of exposure and outcomes.

1.3 Objectives

The objectives of the population pharmacokinetic analysis included:

(a) Compare the exposure of telavancin administered using the priordosing regimen (10 mg/kg QD) and the new dosing regimen (7.5 mg QD) overa range of weights and renal function by simulating exposures using apopulation PK model;

(b) Compare the exposure of telavancin administered using the priordosing regimen (10 mg/kg QD) and the new dosing regimen (7.5 mg/kg QD)in a subpopulation of subjects with higher exposures (obese subjectswith impaired renal function and in HABP/VABP subjects with impairedrenal function);

(c) Estimate the likelihood of mortality, AKI and cure for the prior andnew dosing regimens using a logistic model of exposure vs. outcomes; and

(d) Estimate the likelihood of mortality, AKI and cure for the prior andnew dosing regimens using a logistic model of exposure vs. outcomes invarious sub-populations of interest (underweight subjects, obesesubjects with impaired renal function and HABP/VABP subjects withimpaired renal function.

1.4 Analysis Assumptions

The assumptions underlying this analysis were as follows:

(a) A hierarchical (population) model can account for the two levels ofvariability inherent in repeated measurement designs-inter-individualand intra-individual variability;

(b) The pharmacokinetic parameters are log-normally distributed;

(c) The random effects describing inter-individual variability (η_(ij))in pharmacokinetic parameters are independent, normally distributed withmean zero and a variance ω²; and

-   -   (d) The random effects describing intra-individual variability        or residual error (ε_(ij)) are independent, normally distributed        with mean zero and a variance σ².

1.5 Methods

1.5.1 Software and Platform

Data management and calculation of simulated exposures were carried outusing R version 3.0.2 (The R project for Statistical Computing,http://www.r-project.org). PK predictions were generated using NONMEMversion 7.2 (ICON plc, Dublin, Ireland) on a Windows 7 platform with thegfortran compiler version 4.6.0.

1.5.2 Telavancin Population PK Model

A population PK model for telavancin was developed using the combineddatasets from Phase 1, 2 and Phase 3 HABP/VABP and cSSSI studies whereplasma concentrations of telavancin were assayed in patients. Data wascollated from 1346 subjects, 863 males and 483 females (7262 plasmasamples) ranging in age from 18 to 100, with measured body weightsbetween 33.6 to 314 kg, calculated BMI between 12.3 and 94 kg/m², andcreatinine clearances (Cockcroft-Gault at screening using ideal bodyweight) between 3 and 150 mL/min. The model provided the following:

Pharmacokinetic parameter Combined model CL, liters/h 1.15 ·(CrCl/99)^(0.454) · (AGE/46) ^(0.173) · (WT/77) ^(0.352) · GEND · CSSSI1V₁, liters 6.11 · (CrCl/99)^(−0.214) · (AGE/46) ^(0.229) · (WT/77)^(0.847) Q, liters/h 4.72 · (CrCl/99)^(0.211) · CSSSI2 V₂, liters 6.46 ·(CrCl/99)^(0.127) · (AGE/46) ^(0.381) · (WT/77) ^(0.548) · CSSSI3 GEND =1 for males, 0.933 for females CSSSI1 = 1 for uninfected or HAP, 0.946for cSSSI subject CSSSI2 = 1 for uninfected or HAP, 1.62 for cSSSIsubject CSSSI3 = 1 for uninfected, 1.14 for cSSSI subject PopulationBetween subject Model OFV estimate ± SE variability (%) Final Model34523.584 CL (L/hr) 1.15 ± 0.04 29.8 V1 (L) 6.11 ± 0.23 42.1 Q (L/hr)4.72 ± 0.34 38.1 V2 (L) 6.46 ± 0.22 29.5 Residual variabilityProportional error 17% Additive error 0.36 μg/mL

1.5.3 Simulation of Telavancin Exposures in Phase 3 all-Treated Subjects

Telavancin PK profiles were simulated for each Phase 3 subject using theestimated PK parameters, inter-individual and residual variabilitydetermined during the population PK analysis based on the administereddose as recorded in the dataset. The individually estimated PKparameters were determined based upon the specific inter-individualerrors for each subject determined using nonlinear mixed effectanalysis.

The exposure for the new dosing regimen was simulated by 1) reducing theAKIT and RATE (dosage amount and dosing rate) in the NONMEM datafile by25%, 2) reducing the AKIT and RATE by an additional 50% in subjectsdosed Q48h (CrCl<30 mL/min) and reducing the II (dosing interval) to 24hours and 3) recalculating the AKIT and RATE by multiplying the recordedDOSE (in mg/kg) by 100 for subjects with weight >100 kg. 100 simulationswere performed for each dataset of 1771 subjects using the SIMULATEcommand in NONMEM.

Steady state plasma concentrations at 0, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8,12, 18, 24, 36 and 48 hours after the infusion of telavancin weresimulated for each subject using the prior and new dosing regimens, withexposure over 24 hours calculated using the linear trapezoidal method.

1.5.4 Comparison of Simulated Exposures to Telavancin

AUC_(0-24h) values for the prior dosing regimen and the new dosingregimen were compared by determining the fraction of simulated subjectswith exposures above a cutpoint of 767 μg·hr/mL (based on classificationand regression tree analysis), and the fraction of subjects withexposures below 219 μg·hr/mL (based on a target attainment ratio of 219and a MIC100 of 1 μg/mL). Values were determined for each simulatedclinical trial (n=100), and presented as a mean and standard deviation.

A statistical model of the relationship between exposure and outcomedetermined using logistic regression analysis (see Example 3) was usedto calculate the probability of mortality, AKI or cure for eachsimulated subject based on their exposure. The estimated fittedparameters for the logit function for each relationship between exposureand outcome was used, irrespective of statistical significance. The meanvalues for each outcome were calculated for each simulated trial (n=100)for the prior and new dosing regimens.

The relative risk (RR) for each outcome between the new dosing regimenrelative to the prior dosing regimen was calculated for each simulatedtrial using the mean probability for each outcome.

${{Relative}\mspace{14mu} {risk}} = \frac{p\left( {event}_{alternative} \right)}{p\left( {event}_{current} \right)}$

The process was repeated for HABP/VABP subjects with renal impairment(CrCl≦50 mL/min).

The number of subjects needed to treat (NNT), i.e. the number ofadditional subjects treated with the new regimen required to spare onesubject a change in outcome (death, AKI, reduced cure) was calculatedfor each simulated trial.

${NNT} = \frac{1}{{p\left( {event}_{current} \right)} - {p\left( {event}_{alternative} \right)}}$

The mean and standard deviation values for each outcome were calculatedfor all simulated clinical trials to evaluate the effect of variabilityin exposure on the number needed to treat.

1.5.6 Prior Dosing Guidelines for Telavancin

For subjects with normal renal function, the prior dosing guidelinesstate that telavancin should be administered IV at a dose of 10 mg/kg,in either 5% dextrose injection (D5W), sterile water for injection, or0.9% sodium chloride; in 100 to 250 mL over 60 minutes, once every 24hours. A dosage adjustment is required for subjects whose creatinineclearance is <50 mL/min, as listed in Table 1-1.

TABLE 1-1 Prior Telavancin Dosage Adjustment in Subjects with RenalImpairment Creatinine Clearance^(a) (mL/min) Telavancin DosageRegimen >50  10 mg/kg every 24 hours 30-50 7.5 mg/kg every 24 hours <30 10 mg/kg every 48 hours ^(a)Calculate using the Cockcroft-Gault formulaand ideal body weight (IBW). Use actual body weight if it is less thanIBW

1.5.7 New Dosing Guidelines for Telavancin

For subjects with normal renal function, the new dosing guidelines ofthis example provide that telavancin should be administered IV at a doseof 7.5 mg/kg, in e.g., either 5% dextrose injection (D5W), sterile waterfor injection, or 0.9% sodium chloride; in 100 to 250 mL over 60minutes, once every 24 hours. The daily telavancin dose should notexceed the dose at 100 kg for any patient weighing more than 100 kg (750mg, 562 mg or 375 mg). A dosage adjustment is required for subjectswhose creatinine clearance is ≦50 mL/min, as listed in Table 1-2.

TABLE 1-2 Telavancin Dosage Adjustment in Subjects with Renal Impairmentfor New Dosing Regimen Creatinine Maximum Clearance^(a) (mL/min)Telavancin Dosage Regimen Dose >50  7.5 mg/kg every 24 hours 750 mg30-50 5.625 mg/kg every 24 hours 562 mg <30  3.75 mg/kg every 24 hours375 mg ^(a)Calculate using the Cockcroft-Gault formula and ideal bodyweight (IBW). Use actual body weight if it is less than IBW

1.6 Results

1.6.1 Data

The data for the simulations was based on 1771 subjects from Studies0015, 0017, 0018 and 0019. One subject (0018-38160-2518) did not have arecorded value for baseline CrCl and was removed from the simulation.One subject (0015-06013-4221) did not have a recorded value for weightand was removed from the simulation. The population consisted of 750HABP/VABP subjects and 1021 cSSSI subjects, 706 females and 1065 males,ranging in age from 18 to 100 with measured body weights from 30 to 314kg, calculated BMI between 11 and 94 kg/m², and creatinine clearances(Cockcroft-Gault at screening) between 5 and 369 mL/min (Table 1-3).

TABLE 1-3 Demographics of Simulated Population mean ± SD (range)HABP/VABP cSSSI Total n 750 1021 1771 AGE (years) 62 ± 19 (18, 100) 49 ±16 (18, 96)  54 ± 18 (18, 100) WEIGHT (kg) 72 ± 21 (30, 226) 86 ± 27(39, 314) 80 ± 26 (30, 314) HEIGHT (cm) 168 ± 10 (122, 198) 170 ± 10(127, 201) 169 ± 10 (122, 201) BMI (kg/m²) 26 ± 7 (11, 88)  30 ± 9 (13,94)  28.0 ± 8.3 (11, 94)  CrCl (mL/min) 84 ± 57 (5, 369)  95 ± 39 (6,298)  91 ± 47 (5, 369)  SEX F = 261, M = 489 F = 445, M = 576 F = 706, M= 1065 MORTALITY Y = 178, N = 572, Y = 9, N = 1012, Y = 187, N = 1584AKI Y = 171, N = 542, Y = 120, N = 871, Y = 291, N = 1413, UNKNOWN = 37UNKNOWN = 30 UNKNOWN = 67 CURE CURE = 442, CURE = 788, CURE = 1230,INDETERMINATE = 96, INDETERMINATE = 46, INDETERMINATE = 142, NOT CURED =0, NOT CURED = 123, NOT CURED = 123, FAILURE = 99, FAILURE = 0, FAILURE= 99, UNKNOWN = 113 UNKNOWN = 64 UNKNOWN = 177

The majority of the subjects had normal renal function (CrCl>80 mL/min)and weighed between 60 and 105 kg (Table 1-4).

TABLE 1-4 Number of Subjects as Defined by Weight and Renal Functionamong the HABP/VABP and cSSSI Phase 3 Population <30 30-50 50-8080-150 >150 N = 1771 mL/min mL/min mL/min mL/min mL/min <60 kg 39 64 7992 24 60-105 kg 93 139 264 597 129 105-150 kg 11 14 56 116 21 >105 kg 34 8 17 1

1.6.2 Simulated Exposure to Telavancin Based Upon Prior Dosing Regimen

Simulated exposures to telavancin increase with increasing body weight(FIG. 1). In subjects with CrCl between 30 and 50 mL/min, the prior doseadjustment for renal impairment maintains exposure similar to theexposure in subjects with normal renal function (FIG. 2). However, forsubjects with CrCl<30 mL/min, the dose of 10 mg/kg Q48h results inhigher exposures to telavancin during the first 24 hours of dosingcompared to the second day. Subjects with CrCl>150 mL/min had simulatedexposures that were comparable to subjects with CrCl between 80 and 150mL/min. FIG. 3A shows the cumulative distribution of AUC_(0-24h) andC_(min) for the prior dosing regimen.

1.6.3 Simulated Exposure to Telavancin Based Upon New Dosing Regimen

A 25% decrease in the dose of telavancin was predicted to reduce theexposure by 25% in all subjects compared to the prior dosing regimen(FIG. 5A and FIG. 5B). The change from Q48h dosing to Q24 dosing at halfthe dose for subjects with CrCl<30 mL/min halves the exposure over thefirst 24 hours. A cap for doses in subjects above 100 kg is anticipatedto limit exposure increases for subjects with weights greater than 100kg. The mean fraction of subjects with an exposure greater than 767μg·hr/mL was reduced from 39% to 10%, whilst the mean number of subjectsin each trial with an exposure less than 219 μg·hr/mL was increased from0% to 1.3% (Table 1-5). The lower threshold of 219 μg·hr/mL was chosenbased upon the AUC₂₄/MIC ratio of 219 which was identified as theexposure target associated with a 1-log reduction in colony counts frombaseline for MRSA in the neutropenic murine-thigh infection modelstudies (see, Hegde S S et al., 2004. Pharmacodynamics of telavancin(TD-6424), a novel bactericidal agent, against gram-positive bacteria.Antimicrob. Agents Chemother. 48:3043-3050), and assuming an upper boundMIC of 1 μg/mL.

TABLE 1-5 Fraction of Simulated Subjects Above an AUC_(0-24 h) Cutpointof 767 μg · hr/mL and Below an AUC/MIC Cutpoint of 219 μg · hr/mL % ofsubjects Dosing regimen with AUC_(0-24 h): 10 mg/kg QD¹ 7.5 mg/kgQD² >767 μg*hr/mL  39 ± 1.2%  10 ± 0.6% <219 μg*hr/mL 0.1 ± 0.1% 1.3 ±0.3% ¹Dose is modified to 7.5 mg/kg QD for patients with CrCl between30-50 mL/min and 10 mg/kg Q48 for patients with CrCl < 30 mL/min ²Doseis modified to 5.625 mg/kg QD and 3.75 mg/kg QD in subjects with CrClbetween 30-50 mL and <30 mL/min, respectively. A maximum dose of 750 mg(or 562 and 375 mg for patients with renal impairment) is employed forsubjects weighing >100 kg.

1.6.4 Exposure in Underweight, Obese cSSSI and Renally ImpairedHABP/VABP Populations

In underweight subjects (weight ≦45 kg, n=48), the new dosing regimen ispredicted to reduce exposure compared to the prior dosing regimen (FIG.5A). The mean fraction of underweight subjects with an exposure greaterthan 767 μg·hr/mL was reduced from 16% to 3%, whilst the mean number ofsubjects in each trial with an exposure less than 219 μg·hr/mL wasincreased from 0.4% to 5.1% (Table 1-6).

TABLE 1-6 Fraction of Simulated Subjects with Weight ≦ 45 kg Above anAUC_(0-24 h) Cutpoint of 767 μg · hr/mL and Below an AUC/MIC Cutpoint of219 μg · hr/mL % of Subjects Dosing regimen with AUC_(0-24 h): 10 mg/kgQD¹ 7.5 mg/kg QD² >767 μg*hr/mL  16 ± 4.2% 3.4 ± 2.3% <219 μg*hr/mL 0.4± 0.9% 5.1 ± 2.8% ¹Dose is modified to 7.5 mg/kg QD for patients withCrCl between 30-50 mL/min and 10 mg/kg Q48 for patients with CrCl < 30mL/min ²Dose is modified to 5.625 mg/kg QD and 3.75 mg/kg QD in subjectswith CrCl between 30-50 mL and <30 mL/min, respectively. A maximum doseof 750 mg (or 562 and 375 mg for patients with renal impairment) isemployed for subjects weighing >100 kg.

In HABP/VABP subjects with severe renal impairment (CrCl<30 mL/min,n=98), modifying the regimen to 5 mg/kg once daily is anticipated toreduce the fraction of subjects with an AUC_(0-24h)>767 μg·hr/mL from64% to 31% (FIG. 4B). The new dosing regimen includes a 25% reductionand daily dosing and employing a maximum daily dose of 375 mg insubjects weighing greater than 100 kg. These modifications areanticipated to reduce the fraction of subjects with an AUC_(0-24h)>767μg·hr/mL from 64% to 13% (FIG. 4C), whilst the mean number of subjectsin each trial with an exposure less than 219 μg·hr/mL was increased from0% to 2.1% (Table 1-7).

TABLE 1-7 Fraction of Simulated HABP/VABP Subjects with CrCl < 30 mL/minAbove an AUC_(0-24 h) Cutpoint of 767 μg · hr/mL and Below an AUC/MICCutpoint of 219 μg · hr/mL % of Subjects Dosing regimen withAUC_(0-24 h): 10 mg/kg QD¹ 7.5 mg/kg QD² >767 μg*hr/mL  64 ± 4.1%  13 ±2.6% <219 μg*hr/mL 0.0 ± 0.0% 2.1 ± 1.4% ¹Dose is modified to 7.5 mg/kgQD for patients with CrCl between 30-50 mL/min and 10 mg/kg Q48 forpatients with CrCl < 30 mL/min ²Dose is modified to 5.625 mg/kg QD and3.75 mg/kg QD in subjects with CrCl between 30-50 mL and <30 mL/min,respectively. A maximum dose of 750 mg (or 562 and 375 mg for patientswith renal impairment) is employed for subjects weighing >100 kg.

1.6.5 Comparison of the Predicted Effect on Outcomes between Prior andNew Dosing Regimen

Table 1-8 describes the probability for each tested outcome for theprior and new dosing regimen based on the logistic regression model (seeExample 3). The new dosing regimen is predicted to have a 23% reductionin the risk of mortality, a predicted 37% reduction in the risk of AKIand a similar likelihood of clinical response at TOC relative to theprior 10 mg/kg QD dosing regimen

TABLE 1-8 Risks for Prior Dosing Regimen and New Dosing Regimen in AllSubjects Dosing Regimen Risk Ratio Incidence % 10 mg/kg QD¹ 7.5 mg/kgQD² (95% CI) Mortality  8.7  6.7 0.77 (0.61, 0.97) AKI 15.7 10.1 0.65(0.54, 0.77) Clinical 78.0 76.4 0.98 (0.95, 1.02) Response at TOC ¹Doseis modified to 7.5 mg/kg QD for patients with CrCl between 30-50 mL/minand 10 mg/kg Q48 for patients with CrCl < 30 mL/min ²Dose is modified to5.625 mg/kg QD and 3.75 mg/kg QD in subjects with CrCl between 30-50 mLand <30 mL/min, respectively. A maximum dose of 750 mg (or 562 and 375mg for patients with renal impairment) is employed for subjectsweighing >100 kg.

Table 1-9 describes the probability for each tested outcome for theprior and new dosing regimen based on the logistic regression model inHABP/VABP subjects with CrCl≦50 mL/min. The likelihood of 28-dayall-cause mortality and AKI are reduced (49% and 22%, respectively)whilst the likelihood of clinical response at TOC is similar to theprior 10 mg/kg QD dosing regimen.

TABLE 1-9 Risks for Prior Dosing Regimen and New Dosing Regimen inHABP/VABP Subjects with CrCl ≦ 50 mL/min Dosing Regimen Risk RatioIncidence % 10 mg/kg QD¹ 7.5 mg/kg QD² (95% CI) Mortality 43.3 21.9 0.51(0.38, 0.67) AKI 21.0 16.4 0.78 (0.54, 1.14) Clinical 58.7 67.0 1.14(1.00, 1.31) Response at TOC ¹Dose is modified to 7.5 mg/kg QD forpatients with CrCl between 30-50 mL/min and 10 mg/kg Q48 for patientswith CrCl < 30 mL/min ²Dose is modified to 5.625 mg/kg QD and 3.75 mg/kgQD in subjects with CrCl between 30-50 mL and <30 mL/min, respectively.A maximum dose of 750 mg (or 562 and 375 mg for patients with renalimpairment) is employed for subjects weighing >100 kg.

Table 1-10 describes the probability for each tested outcome for theprior and new dosing regimen based on the logistic regression model inCSSSI subjects with weight >100 kg. The likelihood of AKI is reduced 71%and the likelihood of clinical response at TOC is similar to the prior10 mg/kg QD dosing regimen.

TABLE 1-10 Risks for Prior Dosing Regimen and New Dosing Regimen incSSSI Subjects with Weight > 100 kg Dose Risk Ratio Incidence % 10 mg/kgQD¹ 7.5 mg/kg QD² (95% CI) AKI 20.5  6.0 0.29 (0.17, 0.51) Clinical 85.488.2 1.03 (0.96, 1.11) Response at TOC ¹Dose is modified to 7.5 mg/kg QDfor patients with CrCl between 30-50 mL/min and 10 mg/kg Q48 forpatients with CrCl < 30 mL/min ²Dose is modified to 5.625 mg/kg QD and3.75 mg/kg QD in subjects with CrCl between 30-50 mL and <30 mL/min,respectively. A maximum dose of 750 mg (or 562 and 375 mg for patientswith renal impairment) is employed for subjects weighing >100 kg.

1.7 Discussion

The objective of this analysis was to simulate the exposure oftelavancin and the predicted effect on outcomes with a new dosingregimen. Simulated exposures for the new dosing regimen are based on thedirect relationship between administered dose and exposure.

The new dosing regimen resulted in changes in the exposure for allsubjects, with consistent exposures over a range of weights and renalfunctions. Morbidly obese and underweight subjects with healthy renalfunction are expected to have the lowest exposures to telavancin. Obesesubjects with renal impairment are predicted to have lower exposurescomparable to non-obese subjects with normal renal function based on thelimited number of renally impaired obese subjects in the patientpopulation (n=42).

The predicted effect on outcomes is based on the logistic regressionanalysis of observed exposures in all Phase 3 trials. The statisticalmodel describing the relationship between exposure and AKI wasstatistically significant. The models describing the relationshipbetween exposure and mortality/cure were not statistically significant.Based on these models, the predicted effect on reducing AKI was greaterthan the effect on mortality and cure.

HABP/VABP subjects with renal impairment (CrCl≦50 mL/min) were shown tohave a significant relationship between exposure and mortality (seeExample 3). In these subjects, the new dosing regimen results in alarger predicted reduction in mortality, and an increased likelihood ofcure.

cSSSI subjects with weight >100 kg were shown to have a significantrelationship between exposure and AKI (see Example 3). In thesesubjects, the new dosing regimen results in a larger predicted reductionin AKI, and an increased likelihood of cure.

1.8 Conclusion

Based on this analysis, a dose reduction of 25%, a maximum dose cap forsubjects weighing greater than 100 kg and QD dosing for subjects withCrCl<30 mL/min is predicted to maintain a consistent range of exposuresacross the range of weights and renal function observed in the Phase 3trials. The change in the dosing regimen is predicted to reduce theincidence of Aki, with smaller reductions in mortality and efficacy.

Rounding the doses to the nearest tenth of a milligram, the daily doseof telavancin suggested by this analysis for a patient based on thepatient's body weight and creatinine clearance are as shown in Table I:

TABLE I Dose of Telavancin Based on Creatinine Clearance and Body WeightCreatinine Clearance Dose of Telavancin Not to Exceed mL/min mg/kgmg/day >50 7.5 750 30-50 5.6 560 <30 3.8 380

Example 2 Simulated Telavancin Exposures in Obese Subjects Using aPopulation PK Model 2.1 Summary

The objective of this analysis was to estimate the exposure oftelavancin in obese subjects (based on World Health Organization (WHO)obesity classification) using a population PK model of telavancin. Bodyweight is a significant covariate on telavancin plasma clearance andvolume of distribution in the population PK model (see, Samara et al.Population pharmacokinetics of telavancin in healthy subjects andpatients with infections. Antimicrobial Agents and Chemother. 2012;56(4):2067-73)). A simulated population of 20,000 normal and obesesubjects (4,000 subjects for each obesity category of normal, pre-obese,obese class I, II and III) with normal renal function (CrCl>80 mL/min)and BMI ranging from 18.5 to 60 kg/m² was generated by sampling (withreplacement) the demographic data from the existing Phase III HAP andcSSSI study data.

The exposure of telavancin in obese subjects between the ages of 18 and60 with normal renal function (CrCl between 80 and 150 mL/min) ispredicted to increase up to 43% in subjects in Obesity Class III(BMI≧40.0 kg/m²) relative to normal subjects (BMI 18.5-24.9 kg/m².

2.2 Introduction

This analysis is designed to estimate the single-dose pharmacokineticsof telavancin in obese subjects. Exposures of telavancin in obesesubjects were estimated using a population PK model of telavancindeveloped from Phase 1, 2 and 3 clinical studies. Subjects wereclassified according to the WHO obesity classification (Normal:18.5-24.9, Pre-Obese 25.0-29.9, Obese Class I: 30.0-34.9, Obese ClassII: 35.0-39.9, Obese Class III: >40.0).

Variability in the exposure to telavancin in obese subjects wasestimated by generating a virtual population of obese subjects with BMIvalues from 18.5 to 45 kg/m² by generating 4,000 subjects from each WHOclassification by sampling (with replacement) from the distribution ofage, BMI and CrCl from the telavancin clinical PK population used todevelop the population PK model. A total of 20,000 subjects were createdand the exposure following the administration of a single dose oftelavancin was simulated.

2.3 Objectives

The objectives of the population pharmacokinetic analysis included:

(a) Characterize the relationship between AUC of telavancin with BMIfollowing a 10 mg/kg dose using a population PK model by simulatingexposures in subjects with a range of BMI values; and

(b) Quantify the magnitude of variability in the AUC of the obesepopulation based on the variability observed in the population PK modelin the adult telavancin population.

2.4 Analysis Assumptions

The assumptions underlying this analysis were as follows:

(a) A hierarchical (population) model can account for the two levels ofvariability inherent in repeated measurement designs-inter-individualand intra-individual variability;

(b) The pharmacokinetic parameters are log-normally distributed;

(c) The random effects describing inter-individual variability (η_(ij))in pharmacokinetic parameters are independent, normally distributed withmean zero and a variance ω²; and

(d) The random effects describing intra-individual variability orresidual error (ε_(ij)) are independent, normally distributed with meanzero and a variance σ².

2.5 Population Pharmacokinetic Model in Obese Subjects

2.5.1 Data

A population PK model for telavancin in adults was developed using thecombined datasets from Phase 1, 2 and Phase 3 HAP and cSSSI studieswhere plasma concentrations of telavancin were assayed in patients(Tables 2-1A and 2-1B). Data was collated from 1,034 subjects, 641 malesand 393 females (7,262 plasma samples) ranging in age from 18 to 100,with measured body weights between 33.6 to 314 kg, calculated BMIbetween 12.3 and 94 kg/m², and creatinine clearances (Cockcroft-Gault atscreening using ideal body weight) between 3 and 150 mL/min.

TABLE 2-1A Summary of Clinical Studies Used in the Population PKAnalysis Clinical Pharmacology Study ID (used Type of as reference)Acronym Study Description PLAC TLV COMP 0027 Healthy 14C-Telavancin(TLV) ADME 6 I6424-(101a) subject Part 1, single dose (0.25-25 mg/kg);17 + 7 25 + 20 PK part 2, 7 day 7.5-12.5-15 mg/kg I6424-(104a) ThoroughQTc; 7.5 and 15 mg/kg 40 40 + 39 40 I6424-(107a) Skin blister fluidpenetration 9 I6424-(108a) Lung fluid penetration 20 I6424-(105a)Intrinsic Healthy elderly Adults, 10 mg/kg 16 I6424-(102a) factor PKHealthy elderly Adults, 12.5 mg/kg  5 6 I6424-(103a) Impaired renalfunction 29 0016 Impaired hepatic function 16 0032 Extrinsic Midazolaminteraction 16 0035 factor PK Aztreonam 2 g and Piperacillin 4 g/ 14 +12 tazobactam 0.5 g interaction 1407 Renal PK Renal function PK 10 mg/kg45 2403 Renal PK Renal impairment PK 10 mg/kg 43 PLAC: The number ofsubjects in the placebo arm. TLV: The number of subjects in thetelavancin treated arm. COMP: The number of subjects in the comparatorarm.

TABLE 2-1B Summary of Clinical Studies Used in the Population PKAnalysis Efficacy and Safety Studies Study ID (used Type of asreference) Acronym Study Description PLAC TLV 16424-(202a) FAST Phase 2,TLV 7.5 mg/kg,  84  85 Non- 4-10 days in inferiority SSTI vs. VANC ormargin antistaphylococcal 20% penicillin 16424-(202b), FAST-2 TLV 7.5mg/kg in  15  17 before dose SSTI vs. VANC or amendmentantistaphylococcal penicillin 16424-(202b), FAST-2 TLV 10 mg/kg in 103 98 after dose SSTI vs. VANC or amendment antistaphylococcal penicillin0017, ATLAS- Phase 3, TLV 7.5 mg/kg,  73  70 before dose 1 Non- 7-14days in amendment inferiority cSSTI vs. VANC 0017, Margin TLV 10 mg/kg,429 433 after dose 10% 7-14 days in amendment cSSTI vs. VANC 0018,ATLAS- TLV 7.5 mg/kg,  20  19 before dose 2 7-14 days in amendment cSSTIvs. VANC 0018, TLV 10 mg/kg, 517 518 after dose 7-14 days in amendmentcSSTI vs. VANC 16424-(203a) Phase 2 S. aureus  60 uncomplicated bloodstream infection 0015 ATTAIN Phase 3, TLV 10 mg/kg, 7-21 372 374 0019Non-inf. days in Hospital 379 378 Margin Acquired Pneumonia 20% vs. VANCPLAC: The number of subjects in the placebo arm. TLV: The number ofsubjects in the telavancin treated arm.

2.5.2 Generation of a Simulated Population of Normal and Obese Subjects

A simulated population was generated using the demographic data from thePhase 1, 2 and 3 studies in telavancin. 20,000 subjects were generatedby sampling (with replacement) from the clinical trial dataset, withsubjects evenly distributed across each of the five categories ofobesity as classified by the WHO (Table 2-2).

4,000 subjects were generated for each of the five categories of obesitybased on BMI by sampling from the demographic data. The BMI of thesimulated subjects was restricted to be between 18.5 and 60 kg/m² toremove extreme outliers in the population. The height and weightcorresponding to the sampled BMI was incorporated into the simulationdataset. The age of the subjects was based on the distribution of agesin the demographic data between 18 and 60. The baseline creatinineclearance of the subjects was based on the distribution of creatinineclearances in the demographic data between 80 and 150 mL/min. Gender wasrandomly assigned using a binomial distribution of males and femaleswith equal probability for each gender. Simulated subjects werespecified as uninfected. Table 2-3 describes the demographiccharacteristics of the simulated population.

All subjects were administered simulated doses of 10 mg/kg as adjustmentfor renal function was not required.

TABLE 2-2 Definition of WHO Obesity Categories WHO ObesityClassification BMI kg/m² Normal 18.5-24.9 Pre-Obese 25.0-29.9 ObeseClass I 30.0-34.9 Obese Class II 35.0-39.9 Obese Class III ≧40.0

2.5.3 Covariates in Adult Model

Covariates that describe the variability in the PK were identified in aprevious population PK analysis of telavancin (see Example 1).

2.5.4 Population PK Model Pharmacokinetic parameter Combined model Cl,liters/h 1.15 · (CrCl/99)^(0.454) · (AGE/46) ^(0.173) · (WT/77) ^(0.352)· GEND · CSSSI1 V₁, liters 6.11 · (CrCl/99)^(−0.214) · (AGE/46) ^(0.229)· (WT/77) ^(0.847) Q, liters/h 4.72 · (CrCl/99)^(0.211) · CSSSI2 V₂,liters 6.46 · (CrCl/99)^(0.127) · (AGE/46) ^(0.381) · (WT/77) ^(0.548) ·CSSSI3 GEND = 1 for males, 0.933 for females CSSSI1 = 1 for uninfectedor HAP, 0.946 for cSSSI subject CSSSI2 = 1 for uninfected or HAP, 1.62for cSSSI subject CSSSI3 = 1 for uninfected, 1.14 for cSSSI subjectPopulation Between subject Model OFV estimate ± SE variability (%) FinalModel 34523.584 Cl (L/hr) 1.15 ± 0.04 29.8 V1 (L) 6.11 ± 0.23 42.1 Q(L/hr) 4.72 ± 0.34 38.1 V2 (L) 6.46 ± 0.22 29.5 Residual variabilityProportional error 17% Additive error 0.36 μg/mL

2.5.5 Simulation of Telavancin Exposures

Telavancin PK profiles were simulated for each obese subject using theestimated PK parameters and inter-individual errors determined duringthe population PK analysis based on the administered dose as recorded inthe dataset. The individually estimated PK parameters for each subjectwere determined based upon the specific intra and inter-individualerrors determined using nonlinear mixed effect analysis.

Individually predicted (IPRED) plasma concentrations at 0, 0.5, 1, 1.5,2, 3, 4, 5, 6, 8, 12, 18, and 24 hours after the infusion of asingle-dose of telavancin were simulated for each subject, with exposureover 24 hours calculated using the linear trapezoidal method. C_(max)was the maximum plasma concentration of telavancin over the 24 hourdosing period.

2.6 Results

2.6.1 Validation of Population PK Model in Obese Subjects

Standard plots (observed vs. predicted values, weighted residuals) wereused to visually evaluate the goodness of fit of the population PK modelin each category for obesity. The number of plasma concentrationmeasurements and the number of subjects between the ages of 18 and 60with a creatinine clearance >80 mL/min used to evaluate the goodness offit is summarized in Table 2-2.

In all five categories, the observed vs. predicted plasma concentrationsof telavancin were comparable to the line of identity (FIG. 6A-E). Inall five categories, the weighted residuals were evenly distributedaround 0 with the majority of residuals between −2 and 2 (FIG. 7A-E).

2.6.2 Demographics of Simulated Obese Subjects

A total of 20,000 PK profiles were simulated in this analysis. Thesimulated individual subject profiles were evenly distributed across thefive categories of obesity with a mean age of 40 and a mean CrCl of 114mL/min (Table 2-3).

TABLE 2-3 Demographics of Simulated Population of Subjects Obese ObeseObese Normal Pre-Obese Class I Class II Class III n 4000 4000 4000 40004000 AGE (years)  40 ± 12  39 ± 12  39 ± 12  39 ± 12  39 ± 12 WEIGHT(kg)  67 ± 10  80 ± 10  92 ± 12 107 ± 14 130 ± 21 BMI (kg/m²) 22.6 ± 1.627.2 ± 1.4 32.2 ± 1.4 36.9 ± 1.4 45.5 ± 5.3 CrCl (mL/min) 112 ± 19 111 ±17 111 ± 17 111 ± 18 112 ± 17 Gender 1958 M, 1986 M, 2011 M, 2015 M,2017 M, 2042 F  2014 F  1989 F  1985 F  1983 F 

2.6.3 Drug Exposure in Obese Subjects

Exposure to telavancin increased in subjects with increasing BMI (Table2-5). FIG. 9 and FIG. 10 show the range of exposures for simulatedsubjects in each obesity category. A simple linear regression model withAUC_(0-24h) as the dependent variable and BMI as the independentvariable estimated that AUC_(0-24h) increases 10.3 μg·hr/mL for everyincrease of 1 kg/m² in BMI while C_(max) increases 1.1 μg/mL for everyincrease of 1 kg/m² in BMI (FIG. 8A and FIG. 8B).

TABLE 2-4 Summary of Linear Regression on Exposure (AUC_(0-24 h) andC_(max)) as a Function of BMI Call: lm(formula = df.AUC$AUC~df.AUC$BMI)Residuals: Min 1Q median 3Q Max −555.89 −117.97 −16.64 100.83 1118.81Coeffiecients: Estimate Std. Error t value Pr(>|t|) (Intercept) 345.16414.8380 71.34 <2e−16 *** df.AUC$BMI  10.3432 0.1426 72.55 <2e−16 *** . .. Signif. codes: 0 ‘***’ 0.001 ‘**’ 0.01 ‘*’ 0.05 ‘.’ 0.1 ‘ ’ 1 Residualstandard error: 169.1 on 19998 degrees of freedom Multiple R-squared:0.2084, Adjusted R-squared: 0.2083 F-statistic: 5263 on 1 and 19998 DF,p-value: <2.2e−16 Call: lm(formula = df.AUC$CMAX~df.AUC$BMI) Residuals:Min 1Q Median 3Q Max −88.069 −21.147 −3.041 17.833 205.064 Coefficients:Estimate Std. Error t value Pr(>|t|) (Intercept) 63.5406 0.8585 74.01<2e−16 *** df.AUC$BMI  1.1015 0.0253 43.54 <2e−16 *** . . . Signif.codes: 0 ‘***’ 0.001 ‘**’ 0.01 ‘*’ 0.05 ‘.’ 0.1 ‘ ’ 1 Residual standarderror: 30 on 19998 degrees of freedom Multiple R-squared: 0.08658,Adjusted R-squared: 0.08653 F-statistic: 1896 on 1 and 19998 DF,p-value: <2.2e−16

The percentage increases in AUC relative to the subjects of normalweight were 11, 19, 30 and 43% for the pre-obese and obese class I, IIand III respectively. The percentage increases in C_(max) relative tothe subjects of normal weight were 8, 14, 21 and 29% for the pre-obeseand obese class I, II and III respectively.

TABLE 2-5 Telavancin Exposure in Simulated Population of Subjects ObeseObese Obese Normal Pre-Obese Class I Class II Class III AUC_(0-24 h) 569± 143 632 ± 156 677 ± 165 737 ± 183 811 ± 200 (μg · hr/mL) C_(max)(μg/mL) 87 ± 25 94 ± 27 99 ± 30 105 ± 32  113 ± 36 

2.7 Discussion

The objective of this analysis was to simulate the exposure oftelavancin following a single 10 mg/kg dose administration in an obesepopulation. Based upon the simulated exposures across a range of BMI,the exposure of obese subjects to telavancin is expected to increasewith BMI. The trend in increased exposures with increased BMI wasapproximately linear with a 9% increase in AUC_(0-24h) and a 6% increasein C_(max) with each obesity category (FIG. 9 and FIG. 10).

2.8 Conclusions

At a dose of 10 mg/kg, the exposure is anticipated to result inincreased plasma exposure to telavancin in the obese population withnormal renal function by 43% (AUC_(0-24h)) and 29% (C_(max)) in thesubjects with BMI>40 kg/m². The increase was predicted to be linear overthe range of BMI and is reflective of the weight-based dosing regimenfor telavancin.

Example 3 Logistic Regression Analysis of Individually PredictedTelavancin Pharmacokinetic Exposure and Outcomes in HABP/VABP and cSSSIPhase 3 Studies 3.1 Summary

The objective of this post-hoc analysis was to quantifyexposure-response relationships between the plasma exposure totelavancin and the following outcomes: 28-day all-cause mortality, acutekidney injury (AKI) and clinical response at test of cure (TOC) in allPhase 3 hospital acquired bacterial pneumonia/ventilator acquiredbacterial pneumonia (HABP/VABP) and complicated skin and skin structuralinfection (cSSSI) patients (Studies 0015, 0019, 0017 and 0018) treatedwith telavancin. Binomial logistic regression analysis was used todetermine the probability of each of the aforementioned outcome measuresas a function of estimated telavancin exposures from a population PKmodel (in subjects where plasma concentrations were measured).

Exposure (AUC_(0-24h)) to telavancin for subjects where plasmaconcentrations were measured was estimated using a population PK modeldeveloped using all clinical data. Individually predicted steady stateexposures were based on measured plasma concentrations collected 4 to 6days after the first dose of telavancin.

In HABP/VABP subjects with renal impairment (CrCl≦50 mL/min), telavancinexposure had a significant impact on the probability of 28-day all-causemortality. Increased exposure was associated with an increasedprobability of death in this patient subpopulation. However, there wasno significant impact on the probability of 28-day all-cause mortalityfor all HABP/VABP subjects.

In all Phase 3 subjects and cSSSI subjects, telavancin exposure had asignificant impact on the probability of AKI, i.e., increased exposurewas associated with an increased probability of AKI. However, inHABP/VABP subjects alone there was no significant impact on theprobability of AKI.

In all Phase 3 subjects, telavancin exposure did not have a significantimpact on the probability of clinical response at TOC.

3.2. Introduction

This analysis was designed to describe the relationship between exposureand response in patients treated with telavancin. Individually predictedexposures of telavancin in Phase 3 subjects where plasma telavancin wasmeasured (n=579) were estimated using a population PK model oftelavancin developed from Phase 1, 2 and 3 clinical studies. Thetelavancin exposure was predicted using the individually estimatedclearance, volume of distribution, intercompartmental clearance andvolume of the secondary compartment for each subject with no residualerror.

This analysis uses a consistent method to predict exposure to telavancinin both HABP/VABP and cSSSI subjects. Exposure to telavancin waspreviously calculated utilizing the linear trapezoidal method based onfour sparse samples from each subject, collected during the first 12(HABP/VABP) or 4 hours (cSSSI).

Logistic regression analysis was used to parameterize the relationshipbetween exposure (AUC_(0-24h)) and the probability of 28-day all-causemortality, AKI (defined as a 50% increase or greater than 0.5 mg/dLincrease in serum creatinine) and clinical response at test of cure(TOC) for all Phase 3 subjects. The analysis was repeated for theindividual HABP/VABP and cSSSI subpopulations.

3.3 Objectives

The objectives of this analysis were:

(a) Identify and characterize the exposure-response relationship betweentelavancin exposure and the following outcomes in Phase 3 trials incSSSI and HABP/VABP:

-   -   (i) 28-day all-cause mortality (HABP/VABP only);    -   (ii) Acute kidney injury (AKI); and    -   (iii) Clinical response at test of cure (TOC).        3.4 Logistic Regression Analysis in Phase 3 Subjects with PK        Data

3.4.1 Data

The data for the analysis was based upon 579 subjects from Studies 0015,0017, 0018 and 0019. The population consisted of 196 HABP/VABP subjectsand 383 cSSSI subjects, 341 males and 238 females, ranging in age from18 to 100 years with measured body weights from 34 to 314 kg, calculatedBMI between 12 and 94 kg/m², and creatinine clearances (Cockcroft-Gaultat screening) between 5 and 367 mL/min (Table 3-1). Of the 373 subjectsin the studies with cSSSI where PK samples were taken, only 1 subjectdied during the clinical trial.

TABLE 3-1 Demographics of Analysis Population Mean ± SD (range)HABP/VABP cSSSI Total n 196 383 579 AGE (years) 63 ± 18 (20, 100) 44 ±15 (18, 89)  51 ± 18 (18, 100) WEIGHT (kg) 76 ± 22 (34, 171) 83 ± 27(39, 314) 81 ± 26 (34, 314) HEIGHT (cm) 169 ± 11 (122, 195) 171 ± 10(140, 200) 170 ± 11 (122, 200) BMI (kg/m²) 26 ± 7 (12, 65)  29 ± 9 (13,94)  27.8 ± 8.3 (12, 94)  CrCl (mL/min) 85 ± 51 (5, 368)  106 ± 35 (18,249)  99 ± 43 (5, 367)  SEX F = 73, M = 123 F = 165, M = 218 F = 238, M= 341 AUC₀₋₂₄  670 ± 231 (273, 1370)  671 ± 206 (247, 1512)  671 ± 214(247, 1512) (μg · hr/mL) MORTALITY Y = 45, N = 151 Y = 1, N = 382 Y =46, N = 533 AKI Y = 39, N = 157 Y = 39, N = 343, Y = 78, N = 500,UNKNOWN = 1 UNKNOWN = 1 CURE CURE = 127, CURE = 322, CURE = 449,INDETERMINATE = 16, INDETERMINATE = 8, INDETERMINATE = 24, NOT CURED =0, NOT CURED = 30, NOT CURED = 30, FAILURE = 28, FAILURE = 0, FAILURE =28, UNKNOWN = 25 UNKNOWN = 23 UNKNOWN = 48

The population PK model for telavancin in adults was developed using thecombined datasets from Phase 1, 2 and Phase 3 HABP/VABP and cSSSIstudies where plasma concentrations of telavancin were assayed inpatients (see Table 2-1A and 2-1B above). Data was collated from 1,034subjects, 641 males and 393 females (7262 plasma samples) ranging in agefrom 18 to 100, with measured body weights between 33.6 to 314 kg,calculated BMI between 12.3 and 94 kg/m², and creatinine clearances(Cockcroft-Gault at screening using ideal body weight) between 3 and 150mL/min.

3.4.2 Software and Platform

Data manipulation and logistic regression analyses were carried outusing R version 3.0.2 (The R project for Statistical Computing,http://www.r-project.org). PK estimated concentrations were generatedusing NONMEM version 7.2 (ICON plc, Dublin, Ireland) on a Windows 7platform with gfortran (the GNU Fortran compiler version 4.6.0).

3.4.3 Prediction of Telavancin Exposures in Phase 3 All-Treated Subjects

Telavancin PK profiles were predicted for each Phase 3 subject where PKsamples were collected (n=579).

The predicted telavancin PK profiles for each subject were generatedusing the individually estimated PK parameters determined during thepopulation PK analysis based on the administered dose as recorded in thedataset. The individually estimated PK parameters for each subject weredetermined based upon the specific intra- and inter-individual errorsdetermined using nonlinear mixed effect analysis.

Steady state plasma concentrations at 0, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8,12, 18, 24, 36 and 48 hours after the infusion of telavancin werecalculated for each subject, with exposure over 24 hours (AUC_(0-24h))calculated using the linear trapezoidal method.

3.4.4 Logistic Regression Analysis Approach

Logistic regression analyses were conducted on the Phase 3 dataset usingindividually predicted exposure (AUC_(0-24h)) and the outcomes ofinterest (28-day all-cause mortality, AKI, and clinical response atTOC). The analysis was performed using the generalized linear modelfunction in R specifying a binomial variance and the logit linkfunction.

The output produced for each logistic regression analysis includesindices of fit (i.e., null and deviance residuals, Akaike's informationcriterion and likelihood ratio test statistics to provide an assessmentof model improvement as additional parameters are included in themodel).

3.5 Results

3.5.1 Validation of Population PK Model in Phase 3 Subjects

Standard plots (observed vs. predicted values) were used to visuallyevaluate the goodness-of-fit of the individually predicted exposures asdetermined using the population PK model compared to the observedexposures based on the four measured plasma concentrations (FIG. 11B).The linear regression fit of observed versus predicted Phase 3 exposureshad an R² of 0.918.

An R² value of 0.92 and 0.933 resulted from the linear regression fit ofthe observed versus predicted values of the HABP/VABP and cSSSIpopulations respectively (FIG. 12A and FIG. 12B).

3.5.2 Exposure-Response Relationship in the Phase 3 Population

Logistic regression models were fit to determine whether predictedexposures from the population PK model could adequately predict theprobability of 28-day all-cause mortality (Table 3-3), AKI (Table 3-4)and clinical response at TOC (Table 3-5) (FIG. 13A-C).

Exposure (AUC_(0-24h)) did not have a significant impact on theprobability of 28-day all-cause mortality (p=0.078) (FIG. 13A).

TABLE 3-3 Summary of Logistic Regression of 28-day All-Cause Mortalityas a Function of Steady State Exposure (AUC_(0-24 h)) in all (HABP/VABPand cSSSI) Phase 3 Subjects Coefficient Estimate Std. Error Pr(>|z|)Odds Ratio Intercept −3.26 0.50 7.46e−11* 0.038 Steady StateAUC_(0-24 h) 1.16e−3 6.63e−4 0.078 1.001 Pearson Chi-squared Goodness ofFit 1.00  Hosmer-Lemeshow Goodness of Fit 0.127 *p < 0.05

Exposure (AUC_(0-24h)) had a significant impact on the probability ofAKI (p<0.001), i.e., with an increase in exposure, there is an increasein the probability of AKI (Table 3-4) (FIG. 13B).

TABLE 3-4 Summary of Logistic Regression of AKI as a Function of SteadyState Exposure (AUC_(0-24 h)) in all Phase 3 Subjects CoefficientEstimate Std. Error Pr(>|z|) Odds Ratio Intercept −3.36 0.41 2.90e−16*0.034 Steady State AUC_(0-24 h) 2.12e−3 5.28e−4 5.79e−05* 1.002 PearsonChi-squared Goodness of Fit 1.00  Hosmer-Lemeshow Goodness of Fit 0.658*p < 0.05

Exposure (AUC_(0-24h)) did not have a significant impact on theprobability of clinical response at TOC (p=0.368) (Table 3-5) (FIG.13C).

TABLE 3-5 Summary of Logistic Regression of Clinical Response at TOC asa Function of Steady State Exposure (AUC_(0-24 h)) in all Phase 3Subjects Coefficient Estimate Std. Error Pr(>|z|) Odds Ratio Intercept0.95 0.33 3.83e−3* 2.596 Steady State AUC_(0-24 h) 4.29e−3 4.77e−4 0.3681.000 Pearson Chi-squared Goodness of Fit 0.127 Hosmer-Lemeshow Goodnessof Fit 0.213 *p < 0.05

3.5.3 Exposure-Response Relationship in the All-Treated HABP/VABPPopulation

Logistic regression models were fit to determine whether predictedexposures from the population PK model could adequately predict theprobability of 28-day all-cause mortality (Table 3-6), AKI (Table 3-7)and clinical response at TOC (Table 3-8) in HABP/VABP subjects.

Exposure (AUC_(0-24h)) did not have a significant impact on theprobability of 28-day all-cause mortality (p=0.066) in HABP/VABPsubjects (FIG. 14A).

TABLE 3-6 Summary of Logistic Regression of 28-day All-Cause Mortalityas a Function of Steady State Exposure (AUC_(0-24 h)) in all HABP/VABPSubjects Coefficient Estimate Std. Error Pr(>|z|) Odds Ratio Intercept−2.12 0.53 7.95e−5** 0.119 Steady State AUC_(0-24 h) 1.33e−3 7.23e−40.066 1.001 Pearson Chi-squared Goodness of Fit 0.236  Hosmer-LemeshowGoodness of Fit 0.022* *p < 0.05

Exposure (AUC_(0-24h)) did not have a significant impact on theprobability of AKI (p=0.123) in HABP/VABP subjects (Table 3-7) (FIG.14B).

TABLE 3-7 Summary of Logistic Regression of AKI as a Function of SteadyState Exposure (AUC_(0-24 h)) in all HABP/VABP Subjects CoefficientEstimate Std. Error Pr(>|z|) Odds Ratio Intercept −2.19 0.56 9.86e−5**0.111 Steady State AUC_(0-24 h) 1.16e−3 7.56e−4 0.123 1.001 PearsonChi-squared Goodness of Fit 0.502 Hosmer-Lemeshow Goodness of Fit 0.151*p < 0.05

Exposure (AUC_(0-24h)) did not have a significant impact on theprobability of clinical response at TOC (p=0.495) in HABP/VABP subjects(Table 3-8) (FIG. 14C).

TABLE 3-8 Summary of Logistic Regression of Clinical Response at TOC asa Function of Steady State Exposure (AUC_(0-24 h)) in all HABP/VABPSubjects Coefficient Estimate Std. Error Pr(>|z|) Odds Ratio Intercept0.31 0.46 0.502 1.364 Steady State AUC_(0-24 h) 4.50e−4 6.60e−4 0.4951.000 Pearson Chi-squared Goodness of Fit 0.003* Hosmer-LemeshowGoodness of Fit 0.042* *p < 0.05

In the subpopulation of HABP/VABP subjects with renal impairment(CrCl≦50 mL/min), exposure (AUC_(0-24h)) had a significant impact on theprobability of 28-day all-cause mortality (p=0.007) (Table 3-9) (FIG.15A).

TABLE 3-9 Summary of Logistic Regression of 28-day All-Cause Mortalityas a Function of Steady State Exposure (AUC_(0-24 h)) in HABP/VABPSubjects with Renal Impairment (CrCl ≦ 50 mL/min) Coefficient EstimateStd. Error Pr(>|z|) Odds Ratio Intercept −3.65 1.22 0.003* 0.026 SteadyState AUC_(0-24 h) 4.23e−3 1.58e−3 7.22e−3* 1.004 Pearson Chi-squaredGoodness of Fit 0.171 Hosmer-Lemeshow Goodness of Fit 0.160 *p < 0.05

3.5.4 Exposure Response Relationship in the All-Treated cSSSI Population

Logistic regression models were fit to determine whether predictedexposures from the population PK model could adequately predict theprobability of AKI (Table 3-10) and clinical response at TOC (Table3-11) in cSSSI subjects. Logistic regression analysis was not performedfor the dependent variable 28-day all-cause mortality in cSSSI subjectsdue to few cSSSI subjects that died during the study. Exposure(AUC_(0-24h)) had a significant impact on the probability of AKI(p<0.001) in cSSSI subjects. Increases in exposure (AUC_(0-24h)) wereassociated with an increase in the probability of AKI (FIG. 16A). In thesubpopulation of cSSSI subjects with weight >100 kg, exposure(AUC_(0-24h)) had a greater magnitude of impact on the probability ofAKI than for subjects with weight <100 kg (FIG. 17A and FIG. 17B).

TABLE 3-10 Summary of Logistic Regression of AKI as a Function of SteadyState Exposure (AUC_(0-24 h)) in all cSSSI Subjects Coefficient EstimateStd. Error Pr(>|z|) Odds Ratio Intercept −4.35 0.59 2.28e−13* 0.013Steady State AUC_(0-24 h) 3.01e−3 7.3e−4 4.11e−5*  1.003 PearsonChi-squared Goodness of Fit 1 Hosmer-Lemeshow Goodness of Fit 0.209 *p <0.05

In cSSSI subjects, exposure (AUC_(0-24h)) does not have a significantimpact on the probability of clinical response at TOC (p=0.557) (Table3-11) (FIG. 16B).

TABLE 3-11 Summary of Logistic Regression of Clinical Response at TOC asa Function of Steady State Exposure (AUC_(0-24 h)) in all cSSSI SubjectsCoefficient Estimate Std. Error Pr(>|z|) Odds Ratio Intercept 1.39 0.483.96e−3* 4.016 Steady State AUC_(0-24 h) 4.11e−4 7.0e−4 0.557 1.000Pearson Chi-squared Goodness of Fit 0.955 Hosmer-Lemeshow Goodness ofFit 0.850 *p < 0.05

3.6 Discussion

Logistic regression analysis methods were used to determine whetherpredicted exposures from the population PK model could adequatelypredict the probability of 28-day all-cause mortality, AKI, and clinicalresponse at TOC. Individually predicted exposures to telavancin werederived from the population PK model for telavancin developed insubjects where PK samples were collected.

The HABP/VABP and cSSSI subjects were combined into a single population(defined as Phase 3 subjects) to increase the number of events. Poolingthe exposure across the different populations was done with AUC_(0-24h)calculated using a complete PK profile (15 timepoints estimated usingthe population PK model) in place of the previous value based on 4sparse samples taken within 12 hours (HABP/VABP) or 4 hours (cSSSI).

Predicted exposure from the population PK model did not have asignificant impact on 28-day all-cause mortality in HABP/VABP subjects.

The logistic regression analysis in HABP/VABP subjects with impairedrenal function (CrCl≦50 mL/min) is consistent with the results of theCART analysis in HABP/VABP subjects with renal impairment. The CARTanalysis demonstrated a greater likelihood of 28-day mortality forpredicted exposures greater than 767 μg·hr/mL.

3.7 Conclusions

In HABP/VABP subjects with renal impairment (CrCl≦50 mL/min), predictedexposure significantly affected the probability of 28-day all-causemortality, i.e., with increased exposure, there was an increase in theprobability of 28-day all-cause mortality. However, in all Phase 3subjects and the subpopulation of HABP/VABP subjects with normal renalfunction, exposure did not have a significant impact on the probabilityof 28-day all-cause mortality.

For all Phase 3 subjects and the subpopulation of cSSSI subjects,exposure (AUC_(0-24h)) demonstrated a significant impact on theprobability of AKI, i.e., with increased exposure, there was an increasein the probability of AKI. Conversely, for the subpopulation ofHABP/VABP subjects, exposure did not significantly impact theprobability of AKI.

For all Phase 3 subjects and the subpopulations of HABP/VABP and cSSSIsubjects, exposure did not significantly affect the probability ofclinical response at TOC.

Example 4 Simulations of Pharmacokinetic Exposure to Telavancin inSubjects with a New Dosing Regimen Based on Formula (i)

The objective of this analysis was to estimate the exposure totelavancin from the prior daily dosing regimen (10 mg/kg QD) and a newdaily dosing regimen based on formula (i) in subjects in various weightand renal function ranges.

Formula (i) was developed using the clearance (CL) parameter developedin the population PK model for telavancin, i.e., CL(hr/L)=1.15·(CrCl/99)^(0.454)·(AGE/46)^(0.173)·(WT/77)^(0.352)·GEND·CSSSI1(See, Example 1). Substituting this parameter into the standard PKequation:

Dose(mg)=AUC_(target)(μg/mL*hr)*Clearance(L/hr)

and keeping the terms relating to weight and creatinine clearanceprovided formula (i):

Dose(mg)=AUC_(target)*1.15*(WT/77)^(0.352)*(CrCl/99)^(0.154)  (i)

where:AUC_(target) is the target area under the concentration curve inμg*hr/mL;WT is the weight of the patient in kilograms; andCrCl is the creatinine clearance of the patient in mL/minute.

If desired, the dose calculated by formula (i) can be rounded, forexample, to the nearest milligram, 5 milligrams or 10 milligrams. Toallow for such rounding, formula (I) provides a range of ±5 mg.

A new dosing regimen based on formula (i) was evaluated in simulatedpatients and compared to the prior dosing regimen. Telavancin exposuresfor this new dosing regimen were estimated using the virtual populationof HABP/VABP and cSSSI subjects (n=1771) from Example 1. Steady-stateexposures were estimated based on a total of 100 simulations followingthe administration of telavancin.

In overweight subjects, the new dosing regimen based on formula (i) ispredicted to reduce exposure compared to the prior dosing regimen (FIG.18). Additionally, in subjects with low renal function, the new dosingregimen based on formula (i) is predicted to reduce exposure compared tothe prior dosing regimen (FIG. 19).

While the present invention has been described with reference tospecific aspects or embodiments thereof, it will be understood by thoseof ordinary skilled in the art that various changes can be made orequivalents can be substituted without departing from the true spiritand scope of the invention. Additionally, to the extent permitted byapplicable patent statutes and regulations, all publications, patentsand patent applications cited herein are hereby incorporated byreference in their entirety to the same extent as if each document hadbeen individually incorporated by reference herein.

What is claimed is:
 1. A once-daily dose of telavancin foradministration to a human patient having bacteremia, pneumonia,endocarditis, osteomyelitis, or a prosthetic joint infection caused byStaphylococcus aureus, the dose comprising telavancin or apharmaceutically-acceptable salt thereof in an amount selected from: (a)about 7.5 mg/kg of telavancin (free base equivalents) if the patient hasa creatinine clearance greater than about 50 mL/minute, provided thatthe total dose does not exceed about 750 mg/day; (b) about 5.6 mg/kg oftelavancin (free base equivalents) if the patient has a creatinineclearance between about 30 mL/minute and about 50 mL/minute, providedthat the total dose does not exceed about 560 mg/day; and (c) about 3.8mg/kg of telavancin (free base equivalents) if the patient has acreatinine clearance less than about 30 mL/minute, provided that thetotal dose does not exceed about 380 mg/day.
 2. The dose of claim 1,wherein the patient has a creatinine clearance greater than about 50mL/minute.
 3. The dose of claim 1, wherein the patient has a creatinineclearance between about 30 mL/minute and about 50 mL/minute.
 4. The doseof claim 1, wherein the patient has a creatinine clearance less thanabout 30 mL/minute.
 5. The dose of claim 1, wherein the patient has acreatinine clearance between about 10 mL/minute and less than about 30mL/minute.
 6. The dose of claim 1, wherein the patient has bacteremia.7. The dose of claim 1, wherein the patient has pneumonia.
 8. The doseof claim 1, wherein the patient has endocarditis.
 9. The dose of claim1, wherein the patient has osteomyelitis.
 10. The dose of claim 1,wherein the patient has a prosthetic joint infection.
 11. The dose ofclaim 1, wherein the dose is administered intravenously.
 12. The dose ofclaim 1, wherein the Staphylococcus aureus is methicillin-resistantStaphylococcus aureus.
 13. The dose of claim 1, wherein the telavancinis administered as a hydrochloride salt.
 14. The dose of claim 1,wherein telavancin or a pharmaceutically-acceptable salt thereof isadministered in combination with 2-hydroxypropyl-β-cyclodextrin.
 15. Amethod for administering telavancin to a human patient havingbacteremia, pneumonia, endocarditis, osteomyelitis, or a prostheticjoint infection caused by Staphylococcus aureus, the method comprisingadministering a dose of telavancin or a pharmaceutically-acceptable saltthereof to the patient about once every 24 hours; wherein the dose oftelavancin administered to the patient is selected from claim
 1. 16. Amethod for treating bacteremia, pneumonia, endocarditis, osteomyelitis,or a prosthetic joint infection caused by Staphylococcus aureus in ahuman patient, the method comprising administering a dose of telavancinor a pharmaceutically-acceptable salt thereof to the patient about onceevery 24 hours; wherein the dose of telavancin administered to thepatient is selected from claim
 1. 17. The method of claim 16, whereinthe patient has bacteremia.
 18. The method of claim 16, wherein thepatient has pneumonia.
 19. The method of claim 16, wherein the patienthas endocarditis.
 20. The method of claim 16, wherein the patient hasosteomyelitis.
 21. The method of claim 16, wherein the patient has aprosthetic joint infection.
 22. A once-daily dose of telavancin foradministration to a patient having a creatinine clearance less thanabout 50 mL/minute and having a complicated skin and skin structureinfection caused by Staphylococcus aureus, the dose comprisingtelavancin or a pharmaceutically-acceptable salt thereof in an amountselected from: (a) about 5.6 mg/kg of telavancin (free base equivalents)if the patient has a creatinine clearance between about 30 mL/minute andabout 50 mL/minute, provided that the total dose does not exceed about560 mg/day; and (b) about 3.8 mg/kg of telavancin (free baseequivalents) if the patient has a creatinine clearance less than about30 mL/minute, provided that the total dose does not exceed about 380mg/day.
 23. The dose of claim 22, wherein the patient has a creatinineclearance between about 30 mL/minute and about 50 mL/minute.
 24. Thedose of claim 22, wherein the patient has a creatinine clearance lessthan about 30 mL/minute.
 25. The dose of claim 22, wherein the patienthas a creatinine clearance between about 10 mL/minute and less thanabout 30 mL/minute.
 26. The dose of claim 22, wherein the dose isadministered intravenously.
 27. The dose of claim 22, wherein theStaphylococcus aureus is methicillin-resistant Staphylococcus aureus.28. The dose of claim 22, wherein the telavancin is administered as ahydrochloride salt.
 29. The dose of claim 22, wherein telavancin or apharmaceutically-acceptable salt thereof is administered in combinationwith 2-hydroxypropyl-β-cyclodextrin.
 30. A method for administeringtelavancin to a human patient having a creatinine clearance less thanabout 50 mL/minute and having a complicated skin and skin structureinfection caused by Staphylococcus aureus, the method comprisingadministering a dose of telavancin or a pharmaceutically-acceptable saltthereof to the patient about once every 24 hours; wherein the dose oftelavancin administered to the patient is selected from claim
 22. 31. Amethod for treating complicated skin and skin structure infectionscaused by Staphylococcus aureus in a human patient having a creatinineclearance less than about 50 mL/minute, the method comprisingadministering a dose of telavancin or a pharmaceutically-acceptable saltthereof to the patient about once every 24 hours for about 7 to about 14days; wherein the dose of telavancin administered to the patient isselected from claim
 22. 32. A once-daily dose of telavancin foradministration to a human patient having an infection caused byStaphylococcus aureus, the dose comprising an amount of telavancin (freebase equivalents) in the range defined by formula (I):Dose(mg)=AUC_(target)*1.15*(WT/77)^(0.352)*(CrCl/99)^(0.454)±5.0  (I)wherein: AUC_(target) is a target area under the concentration curveselected from the range of about 220 to about 730 μg*hr/mL; WT is theweight of the patient in kilograms; and CrCl is the creatinine clearanceof the patient in mL/minute.
 33. The dose of claim 32, wherein the doseis rounded to the nearest 10 mg.
 34. The dose of claim 32, wherein theAUC_(target) is 600 μg*hr/mL.
 35. The dose of claim 32, wherein theinfection is selected from bacteremia, pneumonia, endocarditis,osteomyelitis, a prosthetic joint infection or a complicated skin andskin structure infection.
 36. The dose of claim 32, wherein the dose isadministered intravenously.
 37. The dose of claim 32, wherein theStaphylococcus aureus is methicillin-resistant Staphylococcus aureus.38. The dose of claim 32, wherein the telavancin is administered as ahydrochloride salt.
 39. The dose of claim 32, wherein telavancin or apharmaceutically-acceptable salt thereof is administered in combinationwith 2-hydroxypropyl-β-cyclodextrin.
 40. A method for administeringtelavancin to a human patient having an infection caused byStaphylococcus aureus, the method comprising administering a dose oftelavancin or a pharmaceutically-acceptable salt thereof to the patientabout once every 24 hours; wherein the dose comprises an amount oftelavancin (free base equivalents) in the range defined by claim
 32. 41.A method for treating an infection caused by Staphylococcus aureus in ahuman patient, the method comprising administering a dose of telavancinor a pharmaceutically-acceptable salt thereof to the patient about onceevery 24 hours; wherein the dose comprises an amount of telavancin (freebase equivalents) in the range defined by claim
 32. 42. The method ofclaim 41, wherein the infection is bacteremia.
 43. The method of claim41, wherein the infection is pneumonia.
 44. The method of claim 41,wherein the infection is endocarditis.
 45. The method of claim 41,wherein the infection is osteomyelitis.
 46. The method of claim 41,wherein the infection is a prosthetic joint infection.
 47. The method ofclaim 41, wherein the infection is a complicated skin and skin structureinfection.
 48. A once-daily dose of telavancin for administration to ahuman patient having an infection caused by Staphylococcus aureus, thedose comprising an amount of telavancin (free base equivalents) selectedfrom a nomogram wherein each value in the nomogram is in the rangedefined by formula (I):Dose(mg)=AUC_(target)*1.15*(WT/77)^(0.352)*(CrCl/99)^(0.454)±5.0  (I)wherein: AUC_(target) is a target area under the concentration curveselected from the range of about 220 to about 730 μg*hr/mL; WT is theweight of the patient in kilograms; and CrCl is the creatinine clearanceof the patient in mL/minute.
 49. The dose of claim 48, wherein the doseis rounded to the nearest 10 mg.
 50. The dose of claim 48, wherein theAUC_(target) is 600 μg*hr/mL.
 51. The dose of claim 48, wherein theinfection is selected from bacteremia, pneumonia, endocarditis,osteomyelitis, a prosthetic joint infection or a complicated skin andskin structure infection.
 52. The dose of claim 48, wherein the dose isadministered intravenously.
 53. The dose of claim 48, wherein theStaphylococcus aureus is methicillin-resistant Staphylococcus aureus.54. The dose of claim 48, wherein the telavancin is administered as ahydrochloride salt.
 55. The dose of claim 48, wherein telavancin or apharmaceutically-acceptable salt thereof is administered in combinationwith 2-hydroxypropyl-β-cyclodextrin.
 56. A method for administeringtelavancin to a human patient having an infection caused byStaphylococcus aureus, the method comprising administering a dose oftelavancin or a pharmaceutically-acceptable salt thereof to the patientabout once every 24 hours; wherein the dose comprises an amount oftelavancin (free base equivalents) defined by claim
 48. 57. A method fortreating an infection caused by Staphylococcus aureus in a humanpatient, the method comprising administering a dose of telavancin or apharmaceutically-acceptable salt thereof to the patient about once every24 hours; wherein the dose comprises an amount of telavancin (free baseequivalents) defined by claim
 48. 58. The method of claim 57, whereinthe infection is bacteremia.
 59. The method of claim 57, wherein theinfection is pneumonia.
 60. The method of claim 57, wherein theinfection is endocarditis.
 61. The method of claim 57, wherein theinfection is osteomyelitis.
 62. The method of claim 57, wherein theinfection is a prosthetic joint infection.
 63. The method of claim 57,wherein the infection is a complicated skin and skin structureinfection.
 64. A once-daily dose of telavancin for administration to ahuman patient having an infection caused by Staphylococcus aureus, thedose comprising an amount of telavancin (free base equivalents) selectedfrom a nomogram comprising the values: CrCl mg 10 20 30 40 50 70 90 120150 WT 50 210 290 340 390 430 510 570 650 720 60 220 310 370 420 460 540610 690 760 70 240 320 390 440 490 570 640 730 810 90 260 350 420 480530 620 700 800 880 110 280 380 450 520 570 670 750 850 940 130 290 400480 550 610 710 790 910 1000 150 310 420 510 580 640 750 840 950 1050

wherein: WT is the weight of the patient in kilograms (rounded to thenearest value in the nomogram); and CrCl is the creatinine clearance ofthe patient in mL/minute (rounded to the nearest value in the nomogram).65. The dose of claim 64, wherein the infection is selected frombacteremia, pneumonia, endocarditis, osteomyelitis, a prosthetic jointinfection or a complicated skin and skin structure infection.
 66. Thedose of claim 64, wherein the Staphylococcus aureus ismethicillin-resistant Staphylococcus aureus.
 67. The dose of claim 64,wherein the telavancin is administered as a hydrochloride salt.
 68. Thedose of claim 64, wherein telavancin or a pharmaceutically-acceptablesalt thereof is administered in combination with2-hydroxypropyl-β-cyclodextrin.
 69. A method for administeringtelavancin to a human patient having an infection caused byStaphylococcus aureus, the method comprising administering a dose oftelavancin or a pharmaceutically-acceptable salt thereof to the patientabout once every 24 hours; wherein the dose comprises an amount oftelavancin (free base equivalents) defined by claim
 64. 70. A method fortreating an infection caused by Staphylococcus aureus in a humanpatient, the method comprising administering a dose of telavancin or apharmaceutically-acceptable salt thereof to the patient about once every24 hours; wherein the dose comprises an amount of telavancin (free baseequivalents) defined by claim
 64. 71. The method of claim 70, whereinthe infection is bacteremia.
 72. The method of claim 70, wherein theinfection is pneumonia.
 73. The method of claim 70, wherein theinfection is endocarditis.
 74. The method of claim 70, wherein theinfection is osteomyelitis.
 75. The method of claim 70, wherein theinfection is a prosthetic joint infection.
 76. The method of claim 70,wherein the infection is a complicated skin and skin structureinfection.